Substituted cycloalkyls as inhibitors of a beta protein production

ABSTRACT

This invention relates to novel lactams having the Formula (I):  
                 
 
     to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer&#39;s disease and Down&#39;s Syndrome.

FIELD OF THE INVENTION

[0001] This invention relates to novel lactams having drug andbio-affecting properties, their pharmaceutical compositions and methodsof use. These novel compounds inhibit the processing of amyloidprecursor protein and, more specifically, inhibit the production ofAβ-peptide, thereby acting to prevent the formation of neurologicaldeposits of amyloid protein. More particularly, the present inventionrelates to the treatment of neurological disorders related to β-amyloidproduction such as Alzheimer's disease and Down's Syndrome.

BACKGROUND OF THE INVENTION

[0002] Alzheimer's disease (AD) is a degenerative brain disordercharacterized clinically by progressive loss of memory, temporal andlocal orientation, cognition, reasoning, judgment and emotionallystability. AD is a common cause of progressive dementia in humans and isone of the major causes of death in the United States. AD has beenobserved in all races and ethnic groups worldwide, and is a majorpresent and future health problem. No treatment that effectivelyprevents AD or reverses the clinical symptoms and underlyingpathophysiology is currently available (for review see, Dennis J.Selkoe; Cell Biology of the amyloid (beta)-protein precursor and themechanism of Alzheimer's disease, Annu Rev Cell Biol, 1994, 10:373-403).

[0003] Histopathological examination of brain tissue derived uponautopsy or from neurosurgical specimens in effected individuals revealedthe occurrence of amyloid plaques and neurofibrillar tangles in thecerebral cortex of such patients. Similar alterations were observed inpatients with Trisomy 21 (Down's syndrome), and hereditary cerebralhemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tanglesare nonmembrane-bound bundles of abnormal proteinaceous filaments andbiochemical and immunochemical studies led to the conclusion that theirprinciple protein subunit is an altered phosphorylated form of the tauprotein (reviewed in Selkoe, 1994).

[0004] Biochemical and immunological studies revealed that the dominantproteinaceous component of the amyloid plaque is an approximately 4.2kilodalton (kD) protein of about 39 to 43 amino acids. This protein wasdesignated Aβ, β-amyloid peptide, and sometimes β/A4; referred to hereinas Aβ. In addition to its deposition in amyloid plaques, Aβ is alsofound in the walls of meningeal and parenchymal arterioles, smallarteries, capillaries, and sometimes, venules. Aβ was first purified anda partial amino acid reported in 1984 (Glenner and Wong, Biochem.Biophys. Res. Commun. 120: 885-890). The isolation and sequence data forthe first 28 amino acids are described in U.S. Pat. No 4,666,829.

[0005] Compelling evidence accumulated during the last decade revealedthat Aβ is an internal polypeptide derived from a type 1 integralmembrane protein, termed β amyloid precursor protein (APP). β APP isnormally produced by many cells both in vivo and in cultured cells,derived from various animals and humans. β is derived from cleavage of βAPP by as yet unknown enzyme (protease) system(s), collectively termedsecretases.

[0006] The existence of at least four proteolytic activities has beenpostulated. They include β secretase(s), generating the N-terminus ofAβ, α secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γsecretases, generating C-terminal Aβ fragments ending at position 38,39, 40, 42, and 43 or generating C-terminal extended precursors whichare subsequently truncated to the above polypeptides.

[0007] Several lines of evidence suggest that abnormal accumulation ofAβ plays a key role in the pathogenesis of AD. Firstly, Aβ is the majorprotein found in amyloid plaques. Secondly, Aβ is neurotoxic and may becausally related to neuronal death observed in AD patients. Thirdly,missense DNA mutations at position 717 in the 770 isoform of β APP canbe found in effected members but not unaffected members of severalfamilies with a genetically determined (familiar) form of AD. Inaddition, several other β APP mutations have been described in familiarforms of AD. Fourthly, similar neuropathological changes have beenobserved in transgenic animals overexpressing mutant forms of human βAPP. Fifthly, individuals with Down's syndrome have an increased genedosage of β APP and develop early-onset AD. Taken together, theseobservations strongly suggest that Aβ depositions may be causallyrelated to the AD.

[0008] It is hypothesized that inhibiting the production of Aβ willprevent and reduce neurological degeneration, by controlling theformation of amyloid plaques, reducing neurotoxicity and, generally,mediating the pathology associated with Aβ production. One method oftreatment methods would therefore be based on drugs that inhibit theformation of Aβ in vivo.

[0009] Methods of treatment could target the formation of Aβ through theenzymes involved in the proteolytic processing of β amyloid precursorprotein. Compounds that inhibit β or γsecretase activity, eitherdirectly or indirectly, could control the production of Aβ.Advantageously, compounds that specifically target γ secretases, couldcontrol the production of Aβ. Such inhibition of β or γsecretases couldthereby reduce production of Aβ, which, thereby, could reduce or preventthe neurological disorders associated with Aβ protein.

[0010] PCT publication number WO 96/29313 discloses the general formula:

[0011] covering metalloprotease inhibiting compounds useful for thetreatment of diseases associated with excess and/or unwanted matrixmetalloprotease activity, particularly collagenase and or stromelysinactivity.

[0012] Compounds of general formula:

[0013] are disclosed in PCT publication number WO 95/22966 relating tomatrix metalloprotease inhibitors. The compounds of the invention areuseful for the treatment of conditions associated with the destructionof cartilage, including corneal ulceration, osteoporosis, periodontitisand cancer.

[0014] European Patent Application number EP 0652009A1 relates to thegeneral formula:

[0015] and discloses compounds that are protease inhibitors that inhibitAβ production.

[0016] U.S Pat. No. 5703129 discloses the general formula:

[0017] which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamidederivatives that inhibit Aβ production and are useful in the treatmentof Alzheimer's disease.

[0018] Copending, commonly assigned U.S. patent application Ser. No.09/370089 filed Aug. 7, 1999 (equivalent to international applicationPCT US99/17717) discloses lactams of general formula:

[0019] wherein the lactam ring B is substituted by succinamide and acarbocyclic, aryl, or heteroaryl group. These compounds inhibit theprocessing of amyloid precursor protein and, more specifically, inhibitthe production of Aβ-peptide, thereby acting to prevent the formation ofneurological deposits of amyloid protein.

[0020] None of the above references teaches or suggests the compounds ofthe present invention which are described in detail below.

SUMMARY OF THE INVENTION

[0021] One object of the present invention is to provide novel compoundswhich are useful as inhibitors of the production of Aβ protein orpharmaceutically acceptable salts or prodrugs thereof.

[0022] It is another object of the present invention to providepharmaceutical compositions comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltor prodrug form thereof.

[0023] It is another object of the present invention to provide a methodfor treating degenerative neurological disorders comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

[0024] These and other objects, which will become apparent during thefollowing detailed description, have been achieved by the inventors′discovery that compounds of Formula (I):

[0025] or pharmaceutically acceptable salt or prodrug forms thereof,wherein R³, R^(3a), R⁵, R^(5a), R⁶, Q, B, W, X, Y, and Z are definedbelow, are effective inhibitors of the production of Aβ protein.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0026] Thus, in a first embodiment, the present invention provides anovel compound of Formula (I):

[0027] or a stereoisomer, pharmaceutically acceptable salt or prodrugthereof, wherein:

[0028] Q is —(CR⁷R^(7a))_(m)—R⁴,

[0029] —(CR⁷R^(7a))_(m)—CH(OH)—R⁴,

[0030] —(CR⁷R^(7a))_(m)m—NHC(═O)—R⁴,

[0031] —(CR⁷R^(7a))_(n)—S—R⁴,

[0032] —(CR⁷R^(7a))_(n)—O—R⁴,

[0033] —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴,

[0034] —(CR⁷R^(7a))_(n)—S(═O)—R⁴,

[0035] —(CR⁷R^(7a))_(n)—S(═O)₂—R⁴, or

[0036] —(CR⁷R^(7a))_(n)—C(═O)—R⁴;

[0037] m is 1, 2, or 3;

[0038] n is 0, 1, or 2;

[0039] R⁴ is H,

[0040] C₁-C₈ alkyl substituted with 0-3 R^(4a),

[0041] C₂-C₈ alkenyl substituted with 0-3 R^(4a),

[0042] C₂-C₈ alkynyl substituted with 0-3 R^(4a),

[0043] C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),

[0044] C₆-C₁₀ aryl substituted with 0-3 R^(4b), or

[0045] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0046] R^(4a), at each occurrence, is independently selected from H,

[0047] OH, F, Cl, Br, I, CF₃, C₁-C₃ alkyl,

[0048] C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),

[0049] C₆-C₁₀ aryl substituted with 0-3 R^(4b), and

[0050] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0051] R^(4b), at each occurrence, is independently selected from H,

[0052] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0053] S(═O)CH₃, S(═O)₂CH₃,

[0054] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0055] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0056] R⁵ and R^(5a) are combined to form a 3-8 membered carbocyclicmoiety;

[0057] wherein said 3-8 membered carbocyclic moiety is saturated orpartially unsaturated;

[0058] wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)₂—, —N═,—NH—, and —N(R²⁰)—; and

[0059] wherein said 3-8 membered carbocyclic moiety is substituted with0-4 R^(5b);

[0060] additionally, two R^(5b) substituents on adjacent atoms may becombined to form a benzo fused radical; wherein said benzo fused radicalis substituted with 0-4 R²³;

[0061] additionally, two R^(5b) substituents on adjacent atoms may becombined to form a 5 to 6 membered heteroaryl fused radical, whereinsaid 5 to 6 membered heteroaryl fused radical comprises 1 or 2heteroatoms selected from N, O, and S; wherein said 5 to 6 memberedheteroaryl fused radical is substituted with 0-3 R²³;

[0062] additionally, two R^(5b) substituents on the same or adjacentcarbon atoms may be combined to form a C₃-C₆ carbocycle substituted with0-3 R²³;

[0063] R^(5b), at each occurrence, is independently selected from H,

[0064] OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃,

[0065] S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^(14a), C₁-C₄ alkyl, C₂-C₆alkenyl, alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0066] C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,

[0067] C₃-C₆ carbocycle, phenyl, and a

[0068] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur;

[0069] R⁶ is H;

[0070] C₁-C₆ alkyl substituted with 0-3 R^(6a);

[0071] C₃-C₁₀ carbocycle substituted with 0-3 R⁶b; or

[0072] C₆-C₁₀ aryl substituted with 0-3 R^(6b);

[0073] R^(6a), at each occurrence, is independently selected from H,

[0074] C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R^(16,) aryland CF₃;

[0075] R6b, at each occurrence, is independently selected from H,

[0076] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl,

[0077] C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;

[0078] R^(7a), at each occurrence, is independently H or C₁-C₄ alkyl;

[0079] R⁷a, at each occurrence, is independently H or C₁-C₄ alkyl;

[0080] R^(7b) is H, C₁-C₄ alkyl, or (C₁-C₄ alkyl)OC(═O)—;

[0081] Ring B is a 7 membered lactam,

[0082] wherein the lactam is saturated, partially saturated orunsaturated;

[0083] wherein each additional lactam carbon is substituted with 0-2R¹¹; and,

[0084] optionally, the lactam contains a heteroatom selected from —O—,—S—, —S(═O)—, —S(═O)₂—, —N═, —NH—, and —N(R¹⁰)—;

[0085] additionally, two R¹¹ substituents on adjacent atoms may becombined to form a benzo fused radical; wherein said benzo fused radicalis substituted with 0-4 R¹³;

[0086] additionally, two R¹¹ substituents on adjacent atoms may becombined to form a 5 to 6 membered heteroaryl fused radical, whereinsaid 5 to 6 membered heteroaryl fused radical comprises 1 or 2heteroatoms selected from N, O, and S; wherein said 5 to 6 memberedheteroaryl fused radical is substituted with 0-3 R¹³;

[0087] additionally, two R¹¹ substituents on the same or adjacent carbonatoms may be combined to form a C₃-C₆ carbocycle substituted with 0-3R¹³;

[0088] R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,

[0089] S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;

[0090] C₁-C₆ alkyl optionally substituted with 0-3 R^(10a);

[0091] C₆-C₁₀ aryl substituted with 0-4 R^(10b);

[0092] C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or

[0093] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(10b);

[0094] R^(10a), at each occurrence, is independently selected from:

[0095] H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, N₂,

[0096] NR¹⁵R¹⁶, CF₃;

[0097] aryl substituted with 0-4 R^(10b);

[0098] C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); and

[0099] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(10b);

[0100] R^(10b), at each occurrence, is independently selected from H,

[0101] OH, Cl, F, Br, I, CN, N₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0102] S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0103] R¹¹, at each occurrence, is independently selected from

[0104] H, C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;

[0105] C₁-C₆ alkyl optionally substituted with 0-3 R^(11a);

[0106] C₆-C₁₀ aryl substituted with 0-3 R^(11b);

[0107] C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); and

[0108] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(11b);

[0109] R^(11a), at each occurrence, is independently selected from

[0110] H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂,

[0111] NR¹⁵R¹⁶, CF₃;

[0112] phenyl substituted with 0-3 R^(11b);

[0113] C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); and

[0114] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b);

[0115] R^(11b), at each occurrence, is independently selected from H,

[0116] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0117] S(═O)CH₃, S(═O)₂CH₃,

[0118] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0119] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0120] W is a bond or —(CR⁸R^(8a))_(p)—;

[0121] p is 0, 1, 2, 3, or 4;

[0122] R⁸ and R^(8a), at each occurrence, are independently selectedfrom H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈cycloalkyl;

[0123] X is a bond;

[0124] C₆-C₁₀ aryl substituted with 0-3 R^(Xb);

[0125] C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or

[0126] 5 to 10 membered heterocycle substituted with 0-2 R^(Xb);

[0127] R^(Xb), at each occurrence, is independently selected from H,

[0128] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0129] S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy;

[0130] Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;

[0131] t is 0, 1, or 2;

[0132] u is 0, 1, or 2;

[0133] R⁹ and R^(9a), at each occurrence, are independently selectedfrom H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

[0134] V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,

[0135] —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,—S(═O)₂NR^(19b)—,

[0136] —NR^(19b)S(═O)—, —S(═O)NR¹⁹—, —C(═O)O—, or

[0137] —OC (═O)—;

[0138] Z is H;

[0139] C₁-C₈ alkyl substituted with 0-3 R^(12a);

[0140] C₂-C₆ alkenyl substituted with 0-3 R^(12a);

[0141] C₂-C₆ alkynyl substituted with 0-3 R^(12a);

[0142] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0143] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or

[0144] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0145] R^(12a), at each occurrence, is independently selected from

[0146] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶,

[0147] CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,

[0148] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0149] C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,

[0150] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0151] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and

[0152] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0153] R^(12b), at each occurrence, is independently selected from

[0154] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl,

[0155] SCH₃, S(═O)CH₃, S(═O)₂CH₃, aryl, C₃-C₆ cycloalkyl,

[0156] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0157] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0158] R¹³, at each occurrence, is independently selected from

[0159] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0160] N₂, NR¹⁵R¹⁶, and CF₃;

[0161] R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or

[0162] C₃-C₆ cycloalkyl;

[0163] R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;

[0164] R¹⁵, at each occurrence, is independently selected from H,

[0165] C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆alkyl)—S(═O)₂—;

[0166] R¹⁶, at each occurrence, is independently selected from

[0167] H, OH, C₁-C₆ alkyl, benzyl, phenethyl,

[0168] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—;

[0169] R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl,

[0170] aryl substituted by 0-4 R^(17a), or

[0171] —CH₂-aryl substituted by 0-4 R^(17a);

[0172] R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,

[0173] propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃,

[0174] S(O)CH₃, SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;

[0175] R¹⁸, at each occurrence, is independently selected from

[0176] H, C₁-C₆ alkyl, aryl, aryl-CH₂—, aryl-CH₂CH₂—,

[0177] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—;

[0178] R¹⁹, at each occurrence, is independently selected from

[0179] H, OH, C₁-C₆ alkyl, aryl, aryl-CH₂—, aryl-CH₂CH₂—,

[0180] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—;

[0181] R^(19b), at each occurrence, is independently is H or C₁-C₄

[0182] alkyl;

[0183] R²⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,

[0184] S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;

[0185] C₁-C₆ alkyl optionally substituted with 0-3 R^(20a); or

[0186] C₆-C₁₀ aryl substituted with 0-4 R^(20b);

[0187] R^(20a), at each occurrence, is independently selected from H,

[0188] C₁-C₄ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶,

[0189] CF₃, and aryl substituted with 0-4 R^(20b);

[0190] R^(20b), at each occurrence, is independently selected from H,

[0191] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0192] S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄

[0193] haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0194] and

[0195] R²³, at each occurrence, is independently selected from

[0196] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0197] NO₂, NR¹⁵R¹⁶, and CF₃;

[0198] provided when Q is —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴ and R^(7b) is(C₁-C₄

[0199] alkyl)OC(═O)—, then n is 1 or 2; and

[0200] provided when Q is —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴ and n is 0, thenR⁴

[0201] does not contain a —C(═O)— adjacent to —N(R^(7b))—.

[0202] [2] In a preferred embodiment the present invention provides fora compound of Formula (I) or a stereoisomer, pharmaceutically acceptablesalt or prodrug thereof, wherein:

[0203] Q is —(CR⁷R^(7a))_(m)—R⁴,

[0204] —(CR⁷R^(7a))_(m)—CH(OH)—R⁴,

[0205] —(CR⁷R^(7a))_(m)—NHC(═O)—R⁴,

[0206] —(CR⁷R^(7a))_(n)—S—R⁴,

[0207] —(CR⁷R^(7a))_(n)—O—R⁴, or

[0208] —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴;

[0209] m is 1 or 2;

[0210] n is 0 or 1;

[0211] R⁴ is H,

[0212] C₁-C₈ alkyl substituted with 0-3 R^(4a),

[0213] C₂-C₈ alkenyl substituted with 0-3 R^(4a),

[0214] C₂-C₈ alkynyl substituted with 0-3 R^(4a),

[0215] C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),

[0216] C₆-C₁₀ aryl substituted with 0-3 R^(4b), or

[0217] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0218] R^(4a), at each occurrence, is independently selected from H,

[0219] OH, F, Cl, Br, I, CF₃, C₁-C₃ alkyl,

[0220] C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),

[0221] C₆-C₁₀ aryl substituted with 0-3 R^(4b), and

[0222] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0223] R^(4b), at each occurrence, is independently selected from H,

[0224] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0225] S(═O)CH₃, S(═O)₂CH₃,

[0226] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0227] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0228] R⁵ and R^(5a) are combined to form a 3-8 membered carbocyclicmoiety;

[0229] wherein said 3-8 membered carbocyclic moiety is saturated orpartially unsaturated;

[0230] wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and

[0231] wherein said 3-8 membered carbocyclic moiety is substituted with0-4 R^(5b);

[0232] additionally, two R^(5b) substituents on adjacent atoms may becombined to form a benzo fused radical; wherein said benzo fused radicalis substituted with 0-4 R²³;

[0233] additionally, two R^(5b) substituents on adjacent atoms may becombined to form a 5 to 6 membered heteroaryl fused radical, whereinsaid 5 to 6 membered heteroaryl fused radical comprises 1 or 2heteroatoms selected from N, O, and S; wherein said 5 to 6 memberedheteroaryl fused radical is substituted with 0-3 R²³;

[0234] additionally, two R^(5b) substituents on the same or adjacentcarbon atoms may be combined to form a C₃-C₆ carbocycle substituted with0-3 R²³;

[0235] R^(5b), at each occurrence, is independently selected from H,

[0236] OH, Cl, F, Br, I, CN, N₂, CF₃, acetyl, SCH₃,

[0237] S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^(14a), C₁-C₄ alkyl, C₂-C₆

[0238] alkenyl, alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0239] C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,

[0240] C₃-C₆ carbocycle, phenyl, and a

[0241] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur;

[0242] R⁶ is H, methyl, or ethyl;

[0243] R⁷ at each occurrence, is independently H or C₁-C₄ alkyl;

[0244] R^(7a), at each occurrence, is independently H or C₁-C₄ alkyl;

[0245] R^(7b) is H, C₁-C₄ alkyl, or (C₁-C₄ alkyl)OC(═O)—;

[0246] Ring B is selected from:

[0247] R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R^(19,)

[0248] S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;

[0249] C₁-C₆ alkyl optionally substituted with 0-3 R^(10a) ;

[0250] C₆-C₁₀ aryl substituted with 0-4 R^(10b);

[0251] C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or

[0252] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(10b);

[0253] R^(10a), at each occurrence, is independently selected from:

[0254] H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂,

[0255] NR¹⁵R¹⁶, CF₃;

[0256] aryl substituted with 0-4 R^(10b);

[0257] C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); and

[0258] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(10b);

[0259] R^(10b), at each occurrence, is independently selected from H,

[0260] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0261] S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C_(1-C) ₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0262] R¹¹, at each occurrence, is independently selected from

[0263] H, C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, N₂, NR¹⁸R¹⁹, C(═O)R¹⁷,C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;

[0264] C₁-C₆ alkyl optionally substituted with 0-3 R^(11a);

[0265] C₆-C₁₀ aryl substituted with 0-3 R^(11b);

[0266] C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); and

[0267] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(11b);

[0268] R^(11a), at each occurrence, is independently selected from

[0269] H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂,

[0270] NR¹⁵R¹⁶, CF₃;

[0271] phenyl substituted with 0-3 R^(11b);

[0272] C₃-C₆ cycloalkyl substituted with 0-3 R^(11b) ; and

[0273] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b);

[0274] R^(11b), at each occurrence, is independently selected from H,

[0275] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0276] S(═O)CH₃, S(═O)₂CH₃,

[0277] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0278] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0279] W is a bond or —(CH₂)_(p)—;

[0280] p is 1 or 2;

[0281] X is a bond;

[0282] phenyl substituted with 0-2 R^(Xb);

[0283] C₃-C₆ carbocycle substituted with 0-2 R^(Xb); or

[0284] 5 to 6 membered heterocycle substituted with 0-2 R^(Xb);

[0285] R^(Xb), at each occurrence, is independently selected from H,

[0286] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0287] S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkyl,C₁-C₃ haloalkoxy, and C₁-C₃ halothioalkoxy;

[0288] Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R¹⁹)—,

[0289] —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,—S(═O)₂NR^(19b)—,

[0290] —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or

[0291] —OC(═O)—; Z is H;

[0292] C₁-C₈ alkyl substituted with 0-3 R^(12a);

[0293] C₂-C₆ alkenyl substituted with 0-3 R^(12a);

[0294] C₂-C₆ alkynyl substituted with 0-3 R^(12a);

[0295] C₆-C₁₀ aryl substituted with 0-4 R_(12b);

[0296] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or

[0297] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0298] R^(12a), at each occurrence, is independently selected from

[0299] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶,

[0300] CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,

[0301] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0302] C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,

[0303] C₆-C₁₀ aryl substituted with 0-4 R_(12b);

[0304] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and

[0305] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0306] R^(12b), at each occurrence, is independently selected from

[0307] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF_(3,) acetyl,

[0308] SCH₃, S(═O)CH₃, S(═O)₂CH₃,

[0309] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0310] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0311] R¹³, at each occurrence, is independently selected from

[0312] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0313] NO₂, NR¹⁵R¹⁶, and CF₃;

[0314] R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or

[0315] C₃-C₆ cycloalkyl;

[0316] R^(14a)is H, phenyl, benzyl, or C₁-C₄ alkyl;

[0317] R¹⁵, at each occurrence, is independently selected from H,

[0318] C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆alkyl)—S(═O)₂;

[0319] R¹⁶, at each occurrence, is independently selected from

[0320] H, OH, C₁-C₆ alkyl, benzyl, phenethyl,

[0321] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—;

[0322] R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, aryl substituted by 0-4R^(17a), or

[0323] —CH₂-aryl substituted by 0-4 R^(17a);

[0324] R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃,

[0325] S(O)CH₃, SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;

[0326] R¹⁸, at each occurrence, is independently selected from

[0327] H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl,

[0328] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—;

[0329] R^(19,) at each occurrence, is independently selected from

[0330] H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl;

[0331] R^(19b), at each occurrence, is independently is H or C₁-C₄alkyl;

[0332] R²⁰ is C(═O)OR¹⁷;

[0333] R²³, at each occurrence, is independently selected from

[0334] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0335] NO₂, NR¹⁵R¹⁶, and CF₃;

[0336] provided when Q is —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴ and R^(7b)is(C₁-C₄ alkyl)OC(═O)—, then n is 1 or 2; and

[0337] provided when Q is —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴ and n is 0, thenR⁴ does not contain a —C(═O)— adjacent to —N(R^(7b))—.

[0338] [3] In a more preferred embodiment the present invention providesfor a compound of Formula (Ia):

[0339] or a stereoisomer, pharmaceutically acceptable salt or prodrugthereof, wherein:

[0340] Q is —(CHR^(7a))_(m)—R⁴,

[0341] —(CHR^(7a))_(m)—CH(OH)—R⁴,

[0342] —(CHR^(7a))_(m)—NHC(═O)—R⁴,

[0343] —(CHR^(7a))_(n)—S—R⁴,

[0344] —(CHR^(7a))_(n)——O—R⁴, or

[0345] —(CHR^(7a))_(n)—N (R^(7b))—R⁴;

[0346] m is 1 or 2;

[0347] n is 0 or 1;

[0348] R⁴ is H,

[0349] C₁-C₈ alkyl substituted with 0-3 R^(4a),

[0350] C₂-C₈ alkenyl substituted with 0-3 R^(4a),

[0351] C₂-C₈ alkynyl substituted with 0-3 R^(4a),

[0352] C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),

[0353] C₆-C₁₀ aryl substituted with 0-3 R^(4b), or

[0354] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0355] R^(4a), at each occurrence, is independently selected from H,

[0356] OH, F, Cl, Br, I, CF₃, methyl, ethyl,

[0357] C₃-C₁₀ carbocycle substituted with 0-3 R4b,

[0358] C₆-C₁₀ aryl substituted with 0-3 R^(4b), and

[0359] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0360] R^(4b), at each occurrence, is independently selected from H,

[0361] OH, Cl, F, Br, I, CN, N₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0362] S(═O)CH₃, S(═O)₂CH₃,

[0363] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0364] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0365] R⁵ and R⁵a are combined to form a 3-8 membered carbocyclicmoiety;

[0366] wherein said 3-8 membered carbocyclic moiety is saturated orpartially unsaturated;

[0367] wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and

[0368] wherein said 3-8 membered carbocyclic moiety is substituted with0-4 R^(5b);

[0369] additionally, two R^(5b)substituents on adjacent atoms may becombined to form a benzo fused radical; wherein said benzo fused radicalis substituted with 0-4 R²³;

[0370] additionally, two R^(5b)substituents on adjacent atoms may becombined to form a 5 to 6 membered heteroaryl fused radical, whereinsaid 5 to 6 membered heteroaryl fused radical comprises 1 or 2heteroatoms selected from N, O, and S; wherein said 5 to 6 memberedheteroaryl fused radical is substituted with 0-3 R²³;

[0371] additionally, two R⁵b substituents on the same or adjacent carbonatoms may be combined to form a C₃-C₆ carbocycle substituted with 0-3R²³;

[0372] R^(5b), at each occurrence, is independently selected from H,

[0373] OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃,

[0374] S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^(14a), C₁-C₄ alkyl, C₂-C₆alkenyl, alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0375] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—,

[0376] C₃-C₆ carbocycle, phenyl, and a

[0377] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur;

[0378] R^(7a), at each occurrence, is independently H, methyl, or ethyl;

[0379] R^(7b) is H, methyl, ethyl, CH₃OC(═O)—, or CH₃CH₂OC(═O)—;

[0380] Ring B is selected from:

[0381] R¹¹, at each occurrence, is independently selected from

[0382] H, C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, N₂, NR¹⁸R¹⁹,

[0383] C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;

[0384] C₁-C₆ alkyl optionally substituted with 0-3 R^(11a);

[0385] C₆-C₁₀ aryl substituted with 0-3 R^(11b);

[0386] C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); and

[0387] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(11b);

[0388] R^(11a), at each occurrence, is independently selected from

[0389] H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂,

[0390] NR¹⁵R¹⁶, CF₃;

[0391] phenyl substituted with 0-3 R^(11b);

[0392] C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); and

[0393] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b);

[0394] R^(11b) at each occurrence, is independently selected from H,

[0395] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0396] S(═O)CH₃, S(═O)₂CH₃,

[0397] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0398] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0399] W is a bond;

[0400] X is a bond;

[0401] Y is a bond;

[0402] Z is H;

[0403] C₁-C₈ alkyl substituted with 0-3 R^(12a);

[0404] C₂-C₆ alkenyl substituted with 0-3 R^(12a);

[0405] C₂-C₆ alkynyl substituted with 0-3 R^(12a);

[0406] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0407] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or

[0408] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0409] R^(12a), at each occurrence, is independently selected from

[0410] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶,

[0411] CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,

[0412] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0413] C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,

[0414] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0415] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and

[0416] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0417] R^(12b), at each occurrence, is independently selected from

[0418] H, OH, C_(1,) F, Br, I, CN, NO_(2,) NR¹⁵R¹⁶, CF₃, acetyl,

[0419] SCH₃, S(═O)CH₃, S(═O)₂CH₃,

[0420] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0421] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0422] R¹³, at each occurrence, is independently selected from

[0423] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0424] NO₂, NR¹⁵R¹⁶, and CF₃;

[0425] R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or

[0426] C₃-C₆ cycloalkyl;

[0427] R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;

[0428] R¹⁵, at each occurrence, is independently selected from H,

[0429] C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆alkyl)—S(═O)₂—;

[0430] R¹⁶, at each occurrence, is independently selected from

[0431] H, OH, C₁-C₆ alkyl, benzyl, phenethyl,

[0432] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂-;

[0433] R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl,

[0434] aryl substituted by 0-4 R^(17a), or

[0435] —CH₂-aryl substituted by 0-4 R^(17a);

[0436] R^(7a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃, SO₂CH₃,—NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;

[0437] R¹⁸, at each occurrence, is independently selected from

[0438] H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl,

[0439] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—;

[0440] R^(19,) at each occurrence, is independently selected from

[0441] H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl;

[0442] R²³, at each occurrence, is independently selected from

[0443] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0444] NO₂, NR¹⁵R¹⁶, and CF₃;

[0445] provided when Q is —(CHR^(7a))_(n)—N(R^(7b))—R⁴ and R^(7b) is(C₁-C₄ alkyl)OC(═O)—, then n is 1 or 2; and

[0446] provided when Q is —(CHR^(7a))_(n)—N(R^(7b))—R⁴ and n is O, thenR⁴ does not contain a —C(═O)— adjacent to —N(R^(7b))—.

[0447] [4] In a further more preferred embodiment the present inventionprovides for a compound of Formula (Ia) or a stereoisomer,pharmaceutically acceptable salt or prodrug thereof, wherein:

[0448] Q is —(CH₂)_(m)—R⁴,

[0449] —(CH₂)_(m)—CH(OH)—R⁴,

[0450] —(CH₂)_(m)—NHC(═O)—R⁴,

[0451] —(CH₂)_(n)—S—R⁴,

[0452] —(CH₂)_(n)—O-R⁴, or

[0453] —(CH₂)_(n)——N(R^(7b))—R⁴;

[0454] m is 1 or 2;

[0455] n is 0 or 1;

[0456] R⁴ is C₁-C₈ alkyl substituted with 0-3 R^(4a),

[0457] C₂-C₈ alkenyl substituted with 0-3 R^(4a),

[0458] C₂-C₈ alkynyl substituted with 0-3 R^(4a),

[0459] C₃-C₁₀ carbocycle substituted with 0-3 R4b,

[0460] C₆-C₁₀ aryl substituted with 0-3 R^(4b), or

[0461] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R4b;

[0462] R^(4a), at each occurrence, is independently selected from H,

[0463] OH, F, Cl, Br, I, CF₃, methyl,

[0464] C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),

[0465] C₆-C₁₀ aryl substituted with 0-3 R^(4b), and

[0466] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0467] R^(4b), at each occurrence, is independently selected from H,

[0468] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0469] S(═O)CH₃, S(═O)₂CH₃,

[0470] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0471] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0472] R⁵ and R^(5a)are combined to form a 3-8 membered carbocyclicmoiety;

[0473] wherein said 3-8 membered carbocyclic moiety is saturated orpartially unsaturated;

[0474] wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and

[0475] wherein said 3-8 membered carbocyclic moiety is substituted with0-3 R^(5b);

[0476] R5b, at each occurrence, is independently selected from H,

[0477] OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃,

[0478] S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^(14a), C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0479] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R^(7b) is H, methyl,ethyl, CH₃OC(═O)—, or CH₃CH₂OC(═O)—;

[0480] Ring B is selected from:

[0481] R¹¹, at each occurrence, is independently selected from

[0482] H, ═O, NR¹⁸R¹⁹, CF₃;

[0483] C₁-C₄ alkyl optionally substituted with 0-1 R^(11a); phenylsubstituted with 0-3 R^(11b);

[0484] C₃-C₆ carbocycle substituted with 0-3 R^(11b); and

[0485] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl;

[0486] R^(11a), at each occurrence, is independently selected from H,

[0487] C₁₀-C₄ alkyl, OR¹⁴, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenylsubstituted with 0-3 R^(11b);

[0488] R^(11b), at each occurrence, is independently selected from H,OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;

[0489] W is a bond;

[0490] X is a bond;

[0491] Y is a bond;

[0492] Z is H;

[0493] C₁-C₈ alkyl substituted with 0-3 R^(12a);

[0494] C₂-C₆ alkenyl substituted with 0-3 R^(12a); or

[0495] C₂-C₆ alkynyl substituted with 0-3 R^(12a);

[0496] R^(12a), at each occurrence, is independently selected from

[0497] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶,

[0498] CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,

[0499] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0500] C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,

[0501] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0502] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and

[0503] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b); and wherein said 5to 10 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl,indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl,and isoquinolinyl;

[0504] R^(12b), at each occurrence, is independently selected from

[0505] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl,

[0506] SCH₃, S(═O)CH₃, S(═O)₂CH₃,

[0507] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0508] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0509] R¹³, at each occurrence, is independently selected from

[0510] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0511] NO₂, NR¹⁵R¹⁶, and CF₃;

[0512] R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or

[0513] C₃-C₆ cycloalkyl;

[0514] R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;

[0515] R¹⁵, at each occurrence, is independently selected from H,

[0516] C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)—C(═O)—, and (C₁-C₄alkyl)—S(═O)₂—;

[0517] R¹⁶, at each occurrence, is independently selected from

[0518] H, OH, C₁-C₆ alkyl, benzyl, phenethyl,

[0519] (C₁-C₄ alkyl)—C (═O)—, and (C₁-C₄ alkyl)—S(═O)₂—;

[0520] R¹⁸, at each occurrence, is independently selected from

[0521] H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl,

[0522] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—;

[0523] R¹⁹, at each occurrence, is independently selected from

[0524] H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl;

[0525] provided when Q is —(CH₂)_(n)—N(R^(7b))—R⁴ and R^(7b) is (C₁-C₄alkyl)OC(═O)—, then n is 1 or 2; and

[0526] provided when Q is —(CH₂)_(n)—N(R^(7b))—R⁴ and n is 0, then R⁴does not contain a —C(═O)— adjacent to —N(R^(7b))—.

[0527] [5] In a further more preferred embodiment the present inventionprovides:

[0528] Q is —CH₂R⁴, —CH₂CH₂R⁴, —CH₂CH(OH)—R⁴, —CH₂NH-R⁴,

[0529] —CH₂CH₂NHR⁴, —CH₂N(R^(7b))—R⁴, —CH₂NHC(═O)—R⁴, or —NH—R⁴;

[0530] R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a),

[0531] C₂-C₆ alkenyl substituted with 0-3 R^(4a),

[0532] C₂-C₆ alkynyl substituted with 0-3 R^(4a),

[0533] C₃-C₆ carbocycle substituted with 0-3 R^(4b), phenyl substitutedwith 0-3 R^(4b), or

[0534] 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R4b;

[0535] R^(4a), at each occurrence, is independently selected from H,

[0536] OH, F, Cl, Br, I, CF₃, methyl,

[0537] C₃-C₆ carbocycle substituted with 0--3 R^(4b), phenyl substitutedwith 0-3 R^(4b), and

[0538] 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(4b);

[0539] R^(4b), at each occurrence, is independently selected from H,

[0540] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0541] S(═O)CH₃, S(═O)₂CH₃,

[0542] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0543] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0544] R⁵ and R^(5a) are combined to form a 3-6 membered carbocyclicmoiety;

[0545] wherein said 3-6 membered carbocyclic moiety is saturated orpartially unsaturated;

[0546] wherein said 3-6 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—,

[0547] —NH—, and —N(R²⁰)—; and

[0548] wherein said 3-6 membered carbocyclic moiety is substituted with0-2 R^(5b);

[0549] R5b, at each occurrence, is independently selected from H,

[0550] OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, methyl, ethyl,methoxy, ethoxy, allyl, —OCF₃, and —SCF₃;

[0551] R^(7b) is H, methyl, ethyl, CH₃C(═O)—, or CH₃CH₂OC(═O)—;

[0552] Ring B is selected from:

[0553] R¹¹, at each occurrence, is independently selected from

[0554] H, ═O, NR¹⁸R¹⁹, CF₃;

[0555] C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);

[0556] phenyl substituted with 0-3 R^(11b) ;

[0557] C₃-C₆ carbocycle substituted with 0-3 R^(11b); and

[0558] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl;

[0559] R^(11a), at each occurrence, is independently selected from H,methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl,═O, NR¹⁵NR¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b);

[0560] R^(11b), at each occurrence, is independently selected from H,

[0561] OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;

[0562] W is a bond;

[0563] X is a bond;

[0564] Y is a bond;

[0565] Z is H;

[0566] C₁-C₄ alkyl substituted with 0-3 R^(12a);

[0567] C₂-C₄ alkenyl substituted with 0-3 R^(12a); or

[0568] C₂-C₄ alkynyl substituted with 0-3 R^(12a);

[0569] R^(12a), at each occurrence, is independently selected from

[0570] H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,

[0571] S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy;

[0572] R¹³, at each occurrence, is independently selected from

[0573] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0574] NO₂, NR¹⁵R¹⁶, and CF₃;

[0575] R¹⁵, at each occurrence, is independently selected from H,

[0576] C₁-C₄ alkyl, and benzyl;

[0577] R¹⁶, at each occurrence, is independently selected from

[0578] H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl,methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)₂—, and ethyl-S(═O)₂—;

[0579] R¹⁸, at each occurrence, is independently selected from

[0580] H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;

[0581] R¹⁹, at each occurrence, is independently selected from

[0582] H, methyl, ethyl, propyl, and butyl; and

[0583] provided when Q is —NH—R⁴, then R⁴ does not contain a

[0584] —C(═O)— adjacent to —N(R^(7b))—.

[0585] [6] In a further more preferred embodiment the present inventionprovides:

[0586] Q is —CH₂R⁴, —CH₂CH₂R⁴, —CH₂CH(OH)—R⁴, —CH₂NH—R⁴,

[0587] —CH₂CH₂NHR⁴, —CH₂N(R^(7b))—R⁴, —CH₂NHC(═O)—R⁴, or —NH—R⁴;

[0588] R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a),

[0589] C₂-C₆ alkenyl substituted with 0-3 R^(4a),

[0590] C₂-C₆ alkynyl substituted with 0-3 R^(4a),

[0591] C₃-C₆ carbocycle substituted with 0-3 R^(4b), or phenylsubstituted with 0-3 R^(4b);

[0592] R^(4a), at each occurrence, is independently selected from H,

[0593] OH, F, Cl, Br, I, CF₃, methyl,

[0594] C₃-C₆ carbocycle substituted with 0-3 R^(4b),

[0595] phenyl substituted with 0-3 R^(4b), and

[0596] 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(4b); wherein said 5 to 6membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;

[0597] R^(4b), at each occurrence, is independently selected from H,

[0598] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0599] S(═O)CH₃, S(═O)₂CH₃,

[0600] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0601] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0602] R⁵ and R⁵a are combined to form a 3-6 membered carbocyclic moietyselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andperhydro-2H-pyran; wherein said 3-6 membered carbocyclic moiety issubstituted with 0-1 R^(b 5b);

[0603] R^(5b) is selected from H, OH, Cl, F, CN, CF₃, methyl, ethyl,methoxy, ethoxy, allyl, and —OCF₃;

[0604] R^(7b) is H, methyl, ethyl, CH₃OC(═O)—, or CH₃CH₂OC(═O)—;

[0605] Ring B is selected from:

[0606] R¹¹, at each occurrence, is independently selected from

[0607] H, ═O, NR¹⁸R¹⁹;

[0608] C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);

[0609] phenyl substituted with 0-3 R^(11b);

[0610] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl;

[0611] R^(11a), at each occurrence, is independently selected from H,methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O,NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b);

[0612] R^(11b), at each occurrence, is independently selected from H,

[0613] OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;

[0614] W is a bond;

[0615] X is a bond;

[0616] Y is a bond;

[0617] Z is H;

[0618] C₁-C₄ alkyl substituted with 0-1 R^(12a);

[0619] C₂-C₄ alkenyl substituted with 0-1 R^(12a);

[0620] C₂-C₄ alkynyl substituted with 0-1 R^(12a);

[0621] R^(12a), at each occurrence, is independently selected from

[0622] H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,

[0623] S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;

[0624] R¹³, at each occurrence, is independently selected from

[0625] H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,

[0626] Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃;

[0627] R¹⁵, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl;

[0628] R¹⁶, at each occurrence, is independently selected from

[0629] H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;

[0630] R¹⁸, at each occurrence, is independently selected from

[0631] H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;

[0632] R¹⁹, at each occurrence, is independently selected from

[0633] H, methyl, ethyl, propyl, and butyl;

[0634] provided when Q is —NH—R⁴, then R⁴ does not contain a

[0635] —C(═O)— adjacent to —N(R^(7b))—.

[0636] [7] In a further more preferred embodiment the present inventionprovides:

[0637] R⁵ and R^(5a) are combined to form cyclopentyl or cyclohexyl;

[0638] Q is —CH₂CH₃,

[0639] —CH₂CH₂CH₃,

[0640] —CH₂CH₂CH₂CH₃,

[0641] —CH₂CH₂CH₂CH₂CH₃,

[0642] —CH₂CH₂CH₂CH₂CH₂CH₃,

[0643] —CH₂CH(CH₃)₂,

[0644] —CH₂CH₂CH(CH₃)₂,

[0645] —CH₂CH₂CH₂CH(CH₃)₂,

[0646] —CH₂CH₂CH₂CH₂CH(CH₃)₂,

[0647] —CH₂NHCH₂CH₃,

[0648] —CH₂NHCH₂CH₂CH₃,

[0649] —CH₂NHCH₂CH₂CH₂CH₃,

[0650] —CH₂NHCH(CH₃)₂,

[0651] —CH₂NHCH₂CH(CH₃)₂,

[0652] —CH₂NHCH₂CH₂CH(CH₃)₂,

[0653] —CH₂CH(OH)CH₂CH₃,

[0654] —CH₂CH(OH)CH₂CH₂CH₃,

[0655] —CH₂CH(OH)CH₂CH₂CH₂CH₃,

[0656] —CH₂CH(OH)CH(CH₃)₂,

[0657] —CH₂CH(OH)CH₂CH(CH₃)₂,

[0658] —CH₂CH(OH)CH₂CH₂CH(CH₃)₂,

[0659] —CH₂CH(cyclopropyl),

[0660] —CH₂CH₂CH(cyclopropyl),

[0661] —CH₂CH₂CH₂CH(cyclopropyl),

[0662] —CH₂N(C(═O)OCH₂CH₃)CH₂CH₂CH (CH₃)₂,

[0663] —CH₂NHC(═O)—CH₂—(3,5-diF-phenyl),

[0664] —CH₂NHC(═O)CH(OH)CH(CH₃)₂,

[0665] —CH₂NHC(═O)CH(OH)CH₂CH(CH₃)₂,

[0666] —CH₂NHC (═O)CH(OH)CH₂CH₂CH₃,

[0667] —CH₂NHCH₂CH(OH)CH₂CH(CH₃)₂,

[0668] —CH₂NHCH₂CH(OH)CH₂CH₂CH₃,

[0669] —CH₂NHCH₂CH(OH)CH₂CH₂CH₂CH₃,

[0670] —CH₂NHCH₂CH(OH)CH(CH₃)₂,

[0671] —CH₂NHCH₂CH₂—(cyclopropyl),

[0672] —CH₂NHCH₂CH₂—(cyclobutyl),

[0673] —CH₂NHCH₂CH₂—(cyclopentyl),

[0674] —CH₂NHCH₂CH₂—(cyclohexyl),

[0675] —CH₂NHCH₂—(cyclopropyl),

[0676] —CH₂NHCH₂—(cyclobutyl),

[0677] —CH₂NHCH₂—(cyclopentyl),

[0678] —CH₂NHCH₂—(cyclohexyl),

[0679] —CH₂NH—(cyclopropyl),

[0680] —CH₂NH—(cyclobutyl),

[0681] —CH₂NH—(cyclopentyl),

[0682] —CH₂NH—(cyclohexyl),

[0683] —CH₂NHCH₂CH₂—(3,5-diF-phenyl),

[0684] —CH₂NHCH₂—(1,4-diF-phenyl),

[0685] —CH₂CH₂NHCH₂CH(CH₃)₂,

[0686] —CH₂CH₂NHCH₂CH₂CH₃,

[0687] —CH₂CH₂NHCH₂CH₂CH₂CH₃,

[0688] —CH₂CH₂NHCH₂—(cyclopropyl),

[0689] —CH₂CH₂NHCH₂—(cyclobutpyl),

[0690] —CH₂CH₂NHCH₂—(cyclopentyl),

[0691] —CH₂CH₂NHCH₂—(cyclohexyl),

[0692] —NHCH₂CH(OH)CH(CH₃)₂,

[0693] —NHCH₂CH(OH)—(cyclopropyl),

[0694] —NHCH₂CH(OH)—(cyclobutyl),

[0695] —NHCH₂CH(OH)—(cyclopentyl),

[0696] —NHCH₂CH(OH)—(cyclohexyl), or

[0697] —CH₂NHCH₂CH(OH)—(phenyl);

[0698] W is a bond;

[0699] X is a bond;

[0700] Y is a bond;

[0701] Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl,s-butyl, t-butyl, or allyl; R¹¹, at each occurrence, is independentlyselected from

[0702] H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl,

[0703] 4-F-phenyl, (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—,

[0704] 3-F-phenyl, (3-F-phenyl)CH₂—, (3-F-phenyl)CH₂CH₂—,

[0705] 2-F-phenyl, (2-F-phenyl)CH₂—, (2-F-phenyl)CH₂CH₂—,

[0706] 4-Cl-phenyl, (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—,

[0707] 3-Cl-phenyl, (3-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂CH₂—,

[0708] 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—,

[0709] 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—, (3-CH₃-phenyl)CH₂CH₂—,

[0710] 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—, (4-CF₃-phenyl)CH₂CH₂—,pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and

[0711] R¹³, at each occurrence, is independently selected from

[0712] H, F, Cl, OH, —CH₃, —CH₂CH₃, —OCH₃, and —CF₃.

[0713] [8] In a further more preferred embodiment the present inventionprovides for a compound of Formula (I): wherein:

[0714] Q is —(CH₂)_(m)—R⁴,

[0715] —(CH₂)_(m)—CH(OH)—R⁴,

[0716] —(CH2)_(m)—NHC(═O)—R⁴,

[0717] —(CH₂)_(n)—S—R⁴,

[0718] —(CH₂)_(n)—O—R⁴, or

[0719] —(CH₂)_(n)—N(R^(7b))—R⁴;

[0720] m is 1 or 2;

[0721] n is 0 or 1;

[0722] R⁴ is C₁-C₈ alkyl substituted with 0-3 R^(4a),

[0723] C₂-C₈ alkenyl substituted with 0-3 R^(4a),

[0724] C₂-C₈ alkynyl substituted with 0-3 R^(4a),

[0725] C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),

[0726] C₆-C₁₀ aryl substituted with 0-3 R^(4b), or

[0727] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0728] R^(4a), at each occurrence, is independently selected from H,

[0729] OH, F, Cl, Br, I, CF₃, methyl,

[0730] C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),

[0731] C₆-C₁₀ aryl substituted with 0-3 R^(4b), and

[0732] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b);

[0733] R4b, at each occurrence, is independently selected from H,

[0734] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0735] S(═O)CH₃, S(═O)₂CH₃,

[0736] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0737] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0738] R⁵ and R^(5a)are combined to form a 3-8 membered carbocyclicmoiety;

[0739] wherein said 3-8 membered carbocyclic moiety is saturated orpartially unsaturated;

[0740] wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and

[0741] wherein said 3-8 membered carbocyclic moiety is substituted with0-3 R^(5b);

[0742] R^(5b), at each occurrence, is independently selected from H,

[0743] OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃,

[0744] S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^(14a), C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0745] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0746] R^(7b) is H, methyl, ethyl, CH₃OC(═O)—, or CH₃CH₂OC(═O)—;

[0747] Ring B is selected from:

[0748] R¹¹, at each occurrence, is independently selected from

[0749] H, ═O, NR¹⁸R¹⁹, CF₃;

[0750] C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);

[0751] phenyl substituted with 0-3 R^(11b);

[0752] C₃-C₆ carbocycle substituted with 0-3 R^(11b); and

[0753] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl;

[0754] R^(11a), at each occurrence, is independently selected from H,

[0755] C₁-C₄ alkyl, OR¹⁴, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, and phenylsubstituted with 0-3 R^(11b);

[0756] R^(11b), at each occurrence, is independently selected from H,

[0757] OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;

[0758] W is a bond, —CH₂—, —CH₂CH₂—;

[0759] X is a bond;

[0760] phenyl substituted with 0-2 R^(Xb);

[0761] C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or

[0762] 5 to 6 membered heterocycle substituted with 0-2 R^(Xb);

[0763] R^(Xb), at each occurrence, is independently selected from H,

[0764] OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,

[0765] S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁—C₂haloalkoxy;

[0766] Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—,

[0767] —N(R⁹)—, —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,

[0768] —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S (═O)NR^(19b)—, —C(═O)O—, or—OC(═O)—;

[0769] Z is C₁-C₃ alkyl substituted with 1-2 R^(12a);

[0770] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0771] C₃-C₁₀ carbocycle substituted with 0-3 R^(12b); or

[0772] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0773] R^(12a), at each occurrence, is independently selected from

[0774] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0775] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and

[0776] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0777] R^(12b), at each occurrence, is independently selected from

[0778] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl,

[0779] SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,

[0780] C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0781] R¹³, at each occurrence, is independently selected from

[0782] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,and CF₃;

[0783] R¹⁴ is phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or

[0784] C₃-C₆ cycloalkyl;

[0785] R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;

[0786] R¹⁵, at each occurrence, is independently selected from H,

[0787] C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)—C(═O)—, and (C₁-C₄alkyl)—S(═O)₂—;

[0788] R¹⁶, at each occurrence, is independently selected from

[0789] H, OH, C₁-C₆ alkyl, benzyl, phenethyl,

[0790] (C₁-C₄ alkyl)—C(═O)—, and (C₁-C₄ alkyl)—S(═O)₂—;

[0791] R¹⁸, at each occurrence, is independently selected from

[0792] H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl,

[0793] (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—;

[0794] R¹⁹, at each occurrence, is independently selected from

[0795] H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl;

[0796] R^(9b), at each occurrence, is independently selected from

[0797] H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;

[0798] provided when Q is —(CH₂)_(n)—N(R^(7b))—R⁴ and R^(7b) is (C₁-C₄alkyl)OC(═O)—, then n is 1 or 2; and

[0799] provided when Q is —(CH₂)_(n)—N(R^(7b))—R⁴ and n is 0, then R⁴does not contain a —C(═O)— adjacent to —N(R^(7b))—.

[0800] [9] In a further more preferred embodiment the present inventionprovides:

[0801] Q is —CH₂R⁴, —CH₂CH₂R⁴, —CH₂CH(OH)—R⁴, —CH₂NH—R⁴,

[0802] —CH₂CH₂NHR⁴, —CH₂N(R^(7b))—R⁴, —CH₂NHC (═O)—R⁴, or —NH—R⁴;

[0803] R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a),

[0804] C₂-C₆ alkenyl substituted with 0-3 R^(4a),

[0805] C₂-C₆ alkynyl substituted with 0-3 R^(4a),

[0806] C₃-C₆ carbocycle substituted with 0-3 R^(4b),

[0807] phenyl substituted with 0-3 R^(4b), or

[0808] 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(4b);

[0809] R^(4a), at each occurrence, is independently selected from H,

[0810] OH, F, Cl, Br, I, CF₃, methyl,

[0811] C₃-C₆ carbocycle substituted with 0-3 R^(4b),

[0812] phenyl substituted with 0-3 R^(4b), and

[0813] 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(4b);

[0814] R^(4b), at each occurrence, is independently selected from H,

[0815] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH_(3,)

[0816] S(═O)CH₃, S(═O)₂CH₃,

[0817] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0818] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0819] R⁵ and R^(5a) are combined to form a 3-6 membered carbocyclicmoiety;

[0820] wherein said 3-6 membered carbocyclic moiety is saturated orpartially unsaturated;

[0821] wherein said 3-6 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and

[0822] wherein said 3-6 membered carbocyclic moiety is substituted with0-2 R^(5b);

[0823] R^(5b), at each occurrence, is independently selected from H,

[0824] OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, methyl, ethyl,methoxy, ethoxy, allyl, —OCF₃, and —SCF₃;

[0825] R7b is H, methyl, ethyl, CH₃OC(═O)—, or CH₃CH₂OC(═O)—;

[0826] Ring B is selected from:

[0827] R¹¹, at each occurrence, is independently selected from

[0828] H, ═O, NR¹⁸R¹⁹, CF₃;

[0829] C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);

[0830] phenyl substituted with 0-3 R^(11b);

[0831] C₃-C₆ carbocycle substituted with 0-3 R^(11b); and

[0832] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl;

[0833] R^(11a), at each occurrence, is independently selected from H,methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl,═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b);

[0834] R^(11b), at each occurrence, is independently selected from H,

[0835] OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;

[0836] W is a bond, —CH₂—, —CH₂CH₂—;

[0837] X is a bond;

[0838] phenyl substituted with 0-1 R^(Xb);

[0839] C₃-C₆ cycloalkyl substituted with 0-1 R^(Xb); or

[0840] 5 to 6 membered heterocycle substituted with 0-1 R^(Xb);

[0841] R^(Xb) is selected from H, OH, Cl, F, NR¹⁵R^(16,) CF₃, acetyl,

[0842] SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, methoxy,ethoxy, propoxy, and —OCF₃;

[0843] Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—,

[0844] —N(CH₃)—, or —N(CH₂CH₃)—;

[0845] Z is C₁-C₂ alkyl substituted with 1-2 R^(12a);

[0846] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0847] C₃-C₁₀ carbocycle substituted with 0-3 R^(12b); or

[0848] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0849] R^(12a), at each occurrence, is independently selected from

[0850] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0851] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and

[0852] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b);

[0853] R^(12b), at each occurrence, is independently selected from

[0854] H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl,

[0855] SCH₃, S(═O)CH₃, S—(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,

[0856] C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and

[0857] C₁-C₄ haloalkyl-S—;

[0858] R¹³, at each occurrence, is independently selected from

[0859] H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN,

[0860] NO₂, NR¹⁵R¹⁶, and CF₃;

[0861] R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;

[0862] R¹⁵, at each occurrence, is independently selected from H,

[0863] C₁-C₄ alkyl, and benzyl;

[0864] R¹⁶, at each occurrence, is independently selected from

[0865] H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl,methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)₂—, and ethyl-S(═O)₂—;

[0866] R¹⁸, at each occurrence, is independently selected from

[0867] H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;

[0868] R¹⁹, at each occurrence, is independently selected from

[0869] H, methyl, ethyl, propyl, and butyl; and

[0870] provided when Q is —(CH₂)_(n)—N(R^(7b))—R⁴ and R^(7b) is (C₁-C₄alkyl)OC(═O)—, then n is 1 or 2; and

[0871] provided when Q is —(CH₂)_(n)—N(R^(7b))—R⁴ and n is O, then R⁴does not contain a —C(═O)— adjacent to —N(R^(7b))—.

[0872] [10] In a further more preferred embodiment the present inventionprovides:

[0873] Q is —CH₂R⁴, —CH₂CH₂R⁴, —CH₂CH(OH)—R⁴, —CH₂NH—R⁴,

[0874] —CH₂CH₂NHR⁴, —CH₂N(R^(7b)) —R⁴, —CH₂NHC (═O)—R⁴,

[0875] or —NH—R⁴;

[0876] R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a),

[0877] C₂-C₆ alkenyl substituted with 0-3 R^(4a),

[0878] C₂-C₆ alkynyl substituted with 0-3 R^(4a),

[0879] C₃-C₆ carbocycle substituted with 0-3 R^(4b), or

[0880] phenyl substituted with 0-3 R^(4b);

[0881] R^(4a), at each occurrence, is independently selected from H,

[0882] OH, F, Cl, Br, I, CF₃, methyl,

[0883] C₃-C₆ carbocycle substituted with 0-3 R^(4b),

[0884] phenyl substituted with 0-3 R^(4b), and

[0885] 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(4b); wherein said 5 to 6membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;

[0886] R^(4b), at each occurrence, is independently selected from H,

[0887] OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,

[0888] S(═O)CH₃, S(═O)₂CH₃,

[0889] C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,

[0890] C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;

[0891] R⁵ and R^(5a) are combined to form a 3-6 membered carbocyclicmoiety selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and perhydro-2H-pyran; wherein said 3-6 membered carbocyclic moiety issubstituted with 0-1 R^(5b);

[0892] R^(5b) is selected from H, OH, Cl, F, CN, CF₃, methyl, ethyl,methoxy, ethoxy, allyl, and —OCF₃;

[0893] R^(7b) is H, methyl, ethyl, CH₃OC(═O)—, or CH₃CH₂OC(═O)—;

[0894] Ring B is selected from:

[0895] R¹¹, at each occurrence, is independently selected from

[0896] H, ═O, NR¹⁸R¹⁹;

[0897] C₁-C₄ alkyl optionally substituted with 0-1 R^(11a);

[0898] phenyl substituted with 0-3 R^(11b);

[0899] 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl;

[0900] R^(11a), at each occurrence, is independently selected from H,

[0901] methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl,═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b);

[0902] R^(11b), at each occurrence, is independently selected from H,

[0903] OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;

[0904] W is a bond or —CH₂—;

[0905] X is a bond;

[0906] phenyl substituted with 0-1 R^(Xb);

[0907] C₃-C₆ cycloalkyl substituted with 0-1 R^(Xb); or

[0908] 5 to 6 membered heterocycle substituted with 0-1 R^(Xb);

[0909] R^(Xb) is selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl,methyl, ethyl, methoxy, ethoxy, and —OCF₃;

[0910] Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—,

[0911] —N(CH₃)—, or —N(CH₂CH₃)—;

[0912] Z is C₁-C₂ alkyl substituted with 1-2 R^(12a);

[0913] C₆-C₁₀ aryl substituted with 0-4 R^(12b);

[0914] C₃-C₁₀ carbocycle substituted with 0-3 R^(12b); or

[0915] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b); R^(12a), at eachoccurrence, is independently selected from

[0916] C₆-C₁₀ aryl substituted with 0-4 R^(12b));

[0917] C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and

[0918] 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b); and wherein said 5to 10 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl,indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl,and isoquinolinyl;

[0919] R^(12b), at each occurrence, is independently selected from

[0920] H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,

[0921] S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, and —OCF₃;

[0922] R¹³, at each occurrence, is independently selected from

[0923] H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,

[0924] Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃;

[0925] R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;

[0926] R¹⁵, at each occurrence, is independently selected from H,methyl, ethyl, propyl, and butyl;

[0927] R¹⁶, at each occurrence, is independently selected from

[0928] H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;

[0929] R¹⁸, at each occurrence, is independently selected from

[0930] H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;

[0931] R¹⁹, at each occurrence, is independently selected from

[0932] H, methyl, ethyl, propyl, and butyl; and

[0933] provided when Q is —NH—R⁴, then R⁴ does not contain a

[0934] —C(═O)— adjacent to —N(R^(7b))—.

[0935] [11] In a further more preferred embodiment the present inventionprovides:

[0936] R⁵ and R^(5a) are combined to form cyclopentyl or cyclohexyl;

[0937] Q is —CH₂CH₃,

[0938] —CH₂CH₂CH₃,

[0939] —CH₂CH₂CH₂CH₃,

[0940] —CH₂CH₂CH₂CH₂CH₃,

[0941] —CH₂CH₂CH₂CH₂CH₂CH₃,

[0942] —CH₂CH(CH₃)₂,

[0943] —CH₂CH₂CH(CH₃)₂,

[0944] —CH₂CH₂CH₂CH(CH₃)₂,

[0945] —CH₂CH₂CH₂CH₂CH(CH₃)₂,

[0946] —CH₂NHCH₂CH₃,

[0947] —CH₂NHCH₂CH₂CH₃,

[0948] —CH₂NHCH₂CH₂CH₂CH₃,

[0949] —CH₂NHCH(CH₃)₂,

[0950] —CH₂NHCH₂CH(CH₃)₂,

[0951] —CH₂NHCH₂CH₂CH(CH₃)₂,

[0952] —CH₂CH(OH)CH₂CH₃,

[0953] —CH₂CH(OH)CH₂CH₂CH₃,

[0954] —CH₂CH(OH)CH₂CH₂CH₂CH₃,

[0955] —CH₂CH(OH)CH(CH₃)₂,

[0956] —CH₂CH(OH)CH₂CH(CH₃)₂,

[0957] —CH₂CH(OH)CH₂CH₂CH(CH₃)₂,

[0958] —CH₂CH(cyclopropyl),

[0959] —CH₂CH₂CH(cyclopropyl),

[0960] —CH₂CH₂CH₂CH (cyclopropyl),

[0961] —CH₂N(C(═O)OCH₂CH₃)CH₂CH₂CH(CH₃)₂,

[0962] —CH₂NHC(═O)—CH₂-(3,5-diF-phenyl),

[0963] —CH₂NHC(═O)CH(OH)CH(CH₃)₂,

[0964] —CH₂NHC(═O)CH(OH)CH₂CH(CH₃)₂,

[0965] —CH₂NHC(═O)CH(OH)CH₂CH₂CH₃,

[0966] —CH₂NHCH₂CH(OH)CH₂CH(CH₃)₂,

[0967] —CH₂NHCH₂CH(OH)CH₂CH₂CH₃,

[0968] —CH₂NHCH₂CH(OH)CH₂CH₂CH₂CH₃,

[0969] —CH₂NHCH₂CH(OH)CH(CH₃)₂,

[0970] —CH₂NHCH₂CH₂—(cyclopropyl),

[0971] —CH₂NHCH₂CH₂—(cyclobutyl),

[0972] —CH₂NHCH₂CH₂—(cyclopentyl),

[0973] —CH₂NHCH₂CH₂—(cyclohexyl),

[0974] —CH₂NHCH₂—(cyclopropyl),

[0975] —CH₂NHCH₂—(cyclobutyl),

[0976] —CH₂NHCH₂—(cyclopentyl),

[0977] —CH₂NHCH₂—(cyclohexyl),

[0978] —CH₂NH—(cyclopropyl),

[0979] —CH₂NH—(cyclobutyl),

[0980] —CH₂NH—(cyclopentyl),

[0981] —CH₂NH—(cyclohexyl),

[0982] —CH₂NHCH₂CH₂—(3,5-diF-phenyl),

[0983] —CH₂NHCH₂—(1,4-diF-phenyl),

[0984] —CH₂CH₂NHCH₂CH(CH₃)₂,

[0985] —CH₂CH₂NHCH₂CH₂CH₃,

[0986] —CH₂CH₂NHCH₂CH₂CH₂CH₃,

[0987] —CH₂CH₂NHCH₂—(cyclopropyl),

[0988] —CH₂CH₂NHCH₂—(cyclobutpyl),

[0989] —CH₂CH₂NHCH₂—(cyclopentyl),

[0990] —CH₂CH₂NHCH₂—(cyclohexyl),

[0991] —NHCH₂CH(OH)CH(CH₃)₂,

[0992] —NHCH₂CH(OH)—(cyclopropyl),

[0993] —NHCH₂CH(OH)—(cyclobutyl),

[0994] —NHCH₂CH(OH)—(cyclopentyl),

[0995] —NHCH₂CH(OH)—(cyclohexyl), or

[0996] —CH₂NHCH₂CH(OH)—(phenyl);

[0997] W is a bond or —CH₂—;

[0998] X is a bond;

[0999] Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or

[1000] —N(CH₃)—,

[1001] Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,

[1002] 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl,

[1003] 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl,

[1004] 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl,

[1005] 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,

[1006] 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl,

[1007] 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl,

[1008] 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl,

[1009] 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl,

[1010] 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl,

[1011] thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl,

[1012] 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl,

[1013] 1-benzimidazolyl, cyclopropyl, cyclobutyl,

[1014] cyclopentyl, cyclohexyl, morpholino, N-piperinyl,

[1015] phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,

[1016] (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂,

[1017] (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—,

[1018] (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,

[1019] (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—,

[1020] (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—,

[1021] (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,

[1022] (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,

[1023] (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—,

[1024] (3-F-5-Cl-phenyl)CH₂—, (3-Cl-4-F-phenyl)CH₂—,

[1025] (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,

[1026] (4-MeO-phenyl)CH₂—, (2-Me-phenyl)CH₂—,

[1027] (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,

[1028] (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,

[1029] 4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—,

[1030] (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,

[1031] (furanyl)CH₂—,(thienyl)CH₂—, (pyridyl)CH₂—,

[1032] (2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—,

[1033] (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,

[1034] (oxazolyl)CH₂—, (isoxazolyl)CH₂—,

[1035] (1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—,

[1036] (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,

[1037] (cyclohexyl)CH₂—, (morpholino)CH₂—,

[1038] (N-pipridinyl)CH₂—, phenyl-CH₂CH₂—,

[1039] (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,

[1040] (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,

[1041] (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—,

[1042] (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,

[1043] (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,

[1044] (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,

[1045] (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,

[1046] (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,

[1047] (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,

[1048] (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,

[1049] (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl-4-F-phenyl)CH₂CH₂—,

[1050] (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl) CH₂CH₂—,

[1051] (4-MeO-phenyl)CH₂CH₂—, (2-Me-phenyl)CH₂CH₂—,

[1052] (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—,

[1053] (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—,

[1054] (4-MeS-phenyl)CH₂CH₂—, (2-CF₃O-phenyl) CH₂CH₂—,

[1055] (3-CF₃O-phenyl)CH₂CH₂—, (4-CF₃O-phenyl) CH₂CH₂—,

[1056] furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—, (pyridyl)CH₂CH₂—,

[1057] (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,

[1058] (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—,

[1059] (oxazolyl)CH₂CH₂—, (isoxazolyl)CH₂CH₂—,

[1060] (benzimidazolyl)CH₂CH₂—,(cyclopropyl)CH₂CH₂—,

[1061] (cyclobutyl)CH₂CH₂—,(cyclopentyl)CH₂CH₂—,

[1062] (cyclohexyl)CH₂CH₂—,(morpholino)CH₂CH₂—, or

[1063] (N-pipridinyl)CH₂CH₂—;

[1064] R¹¹, at each occurrence, is independently selected from

[1065] H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl,

[1066] 4-F-phenyl, (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—,

[1067] 3-F-phenyl, (3-F-phenyl)CH₂—, (3-F-phenyl)CH₂CH₂—,

[1068] 2-F-phenyl, (2-F-phenyl)CH₂—, (2-F-phenyl)CH₂CH₂—,

[1069] 4-Cl-phenyl, (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—,

[1070] 3-Cl-phenyl, (3-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂CH₂—,

[1071] 4—CH₃-phenyl, (4—CH₃-phenyl)CH₂—, (4—CH₃-phenyl)CH₂CH₂—,

[1072] 3—CH₃-phenyl, (3—CH₃-phenyl)CH₂—, (3—CH₃-phenyl)CH₂CH₂—,

[1073] 4—CF₃-phenyl, (4—CF₃-phenyl)CH₂—, (4—CF₃-phenyl)CH₂CH₂—,

[1074] pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and

[1075] R¹³, at each occurrence, is independently selected from

[1076] H, F, Cl, OH, —CH₃, —CH₂CH₃, —OCH₃, and —CF₃.

[1077] [12] In a further more preferred embodiment the present inventionprovides for a compound of Formula (Ic):

[1078] or a stereoisomer, pharmaceutically acceptable salt or prodrugthereof.

[1079] [13] In a further more preferred embodiment the present inventionprovides for a compound of Formula (Id):

[1080] or a stereoisomer, pharmaceutically acceptable salt or prodrugthereof.

[1081] [14] In a further more preferred embodiment the present inventionprovides for a compound of Formula (Ie):

[1082] or a stereoisomer, pharmaceutically acceptable salt or prodrugthereof.

[1083] [15] In a further more preferred embodiment the present inventionprovides for a compound of Formula (Ie):

[1084] or a stereoisomer, pharmaceutically acceptable salt or prodrugthereof.

[1085] [16] In a further even more preferred embodiment the presentinvention provides for a compound selected from:

[1086]1-{[(3-methylbutyl)amino]methyl}-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclicamide;

[1087]1{[N′-(ethoxycarbonyl)-N′-(3-methylbutyl)amino]methyl}-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclicamide;

[1088]4-{[(3-methylbutyl)amino]methyl}-4-{N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]carbamoyl}-perhydro-2H-pyran;

[1089]1-(2-hydroxy-pentyl)-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclicamide;

[1090]4-{[[(3,5-difluorophenyl)methyl]amido]methyl}-4-{N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]carbamoyl}-perhydro-2H-pyran;

[1091] 2-(S)-hydroxy-3-methyl-N-({[N-(5-methyl-6-oxo (7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl) butanamide;

[1092]2-(S)-hydroxy-4-methyl-N-({[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl)pentanamide;

[1093]2-(3,5-difluorophenyl)-N-({[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl)acetamide;

[1094]N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))({2-[(2-methylpropyl)amino]ethyl}cyclopentyl)carboxamide;

[1095]({2-[(cyclopropylmethyl)amino]ethyl}cyclopentyl)-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;

[1096][({[2-(3,5-difluorophenyl)ethyl]amino}methyl)cyclopentyl]-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;

[1097][({[(1,4-difluorophenyl)methyl]amino}methyl)cyclopentyl]-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;

[1098]({[(2-cyclopentylethyl)amino]methyl}cyclopentyl)-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;

[1099]{[((2S)-2-hydroxy-4-methylpentyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;

[1100]{[((2S)-2-hydroxy-3-methylbutyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;

[1101]{[((2S)-2-cyclohexyl-2-hydroxyethyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;

[1102]1-{[(3-methylbutylamino]methyl}-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl]-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylicamide;

[1103]1-(5-methyl)hexyl-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylicamide;

[1104]1-pentyl-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylicamide;

[1105]1-(2-hydroxypentyl)-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylicamide;

[1106] 2-(S)-hydroxy-3-methyl-N-{[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]methyl}butanamide;

[1107](2S)-N-({[N-(7-fluoro-1-methyl-2-oxo-5-phenyl(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}methyl)-2-hydroxy-3-methylbutanamide;

[1108](2S)-N-({[N-(5-cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}methyl)-2-hydroxy-3-methylbutanamide;

[1109]{[(cyclohexylamino)methyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;

[1110]({[(2-hydroxyhexyl)amino]methyl}cyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;

[1111]({[((2R)-2-hydroxy-2-phenylethyl)amino]methyl}cyclopentyl)-N-{l-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;and

[1112]({[((2S)-2-hydroxy-2-phenylethyl)amino]methyl}cyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide.

[1113] It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment todescribe additional even more preferred embodiments of the presentinvention.

[1114] In a second embodiment, the present invention provides apharmaceutical composition comprising a compound of Formula (I) and apharmaceutically acceptable carrier.

[1115] In a third embodiment, the present invention provides a methodfor the treatment of neurological disorders associated with β-amyloidproduction comprising administering to a host in need of such treatmenta therapeutically effective amount of a compound of Formula (I).

[1116] In a preferred embodiment the neurological disorder associatedwith β-amyloid production is Alzheimer's Disease.

[1117] In a fourth embodiment, the present invention provides a methodfor inhibiting γ-secretase activity for the treatment of a physiologicaldisorder associated with inhibiting γ-secretase activity comprisingadministering to a host in need of such inhibition a therapeuticallyeffective amount of a compound of Formula (I) that inhibits γ-secretaseactivity.

[1118] Thus, the present invention provides a method for inhibitingγ-secretase activity comprising administering to a host in need of suchinhibition a therapeutically effective amount of a compound of Formula(I) that inhibits γ-secretase activity.

[1119] In a preferred embodiment the physiological disorder associatedwith inhibiting γ-secretase activity is Alzheimer's Disease.

[1120] In a fifth embodiment, the present invention provides a compoundof Formula (I) for use in therapy.

[1121] In a preferred embodiment the present invention provides acompound of Formula (I) for use in therapy of Alzheimer's Disease.

[1122] In a sixth embodiment, the present invention provides for the useof a compound of Formula (I) for the manufacture of a medicament for thetreatment of Alzheimer's Disease.

[1123] As used herein, the term “Aβ” denotes the protein designated Aβ,β-amyloid peptide, and sometimes β/A4, in the art. Aβ is anapproximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acidsfound in amyloid plaques, the walls of meningeal and parenchymalarterioles, small arteries, capillaries, and sometimes, venules. Theisolation and sequence data for the first 28 amino acids are describedin U.S. Pat. No. 4,666,829. The 43 amino acid sequence is: 1 Asp Ala GluPhe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met ValGly Gly Val Val 41 Ile Ala Thr

[1124] The term “APP”, as used herein, refers to the protein known inthe art as β amyloid precursor protein. This protein is the precursorfor Aβ and through the activity of “secretase” enzymes, as used herein,it is processed into Aβ. Differing secretase enzymes, known in the art,have been designated β secretase, generating the N-terminus of Aβ, αsecretase cleaving around the 16/17 peptide bond in Aβ, and “γsecretases”, as used herein, generating C-terminal Aβ fragments endingat position 38, 39, 40, 42, and 43 or generating C-terminal extendedprecursors which are subsequently truncated to the above polypeptides.

[1125] The compounds herein described may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms or by synthesis from optically activestarting materials. Many geometric isomers of olefins, C═N double bonds,and the like can also be present in the compounds described herein, andall such stable isomers are contemplated in the present invention. Cisand trans geometric isomers of the compounds of the present inventionare described and may be isolated as a mixture of isomers or asseparated isomeric forms. All chiral, diastereomeric, racemic forms andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

[1126] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e. ═O), then 2 hydrogens on the atom arereplaced.

[1127] When any variable (e.g. R^(5b)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(5b), thensaid group may optionally be substituted with up to two R^(5b) groupsand R^(5b) at each occurrence is selected independently from thedefinition of R^(5b). Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

[1128] When a bond to a substituent is shown to cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[1129] As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C₁-C₆ alkyl”denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred“alkyl” group, unless otherwise specified, is “C₁-C₄ alkyl”.Additionally, unless otherwise specified, “propyl” denotes n-propyl ori-propyl; “butyl” denotes n-butyl, i-butyl, sec-butyl, or t-butyl.

[1130] As used herein, “alkenyl” or “alkenylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain. Examples of “C₂-C₆ alkenyl” include, butare not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl,hexenyl, and the like.

[1131] As used herein, “alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more carbon-carbon triple bonds which may occur in any stablepoint along the chain, such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

[1132] “Alkoxy” or “alkyloxy” represents an alkyl group as defined abovewith the indicated number of carbon atoms attached through an oxygenbridge. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, “alkylthio” or“thioalkoxy” is represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge.

[1133] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo, and iodo. Unless otherwise specified, preferred halo is fluoroand chloro. “Counterion” is used to represent a small, negativelycharged species such as chloride, bromide, hydroxide, acetate, sulfate,and the like.

[1134] “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example -C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, andheptachloropropyl. “Haloalkoxy” is intended to mean a haloalkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy,2,2,2-trifluoroethoxy, and the like. “Halothioalkoxy” is intended tomean a haloalkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge.

[1135] “Cycloalkyl” is intended to include saturated ring groups, havingthe specified number of carbon atoms. For example, “C₃-C₆ cycloalkyl”denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[1136] As used herein, “carbocycle” is intended to mean any stable 3- to7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).Preferred “carbocycle” are cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

[1137] As used herein, “carbocyclic moiety” is intended to mean anystable 3- to 8-membered monocyclic ring of carbon atoms, any of whichmay be saturated or partially unsaturated. Additionally, the 3 to 8membered monocyclic ring of carbon atoms may be contain a heteroatomselected from oxygen, sulphur, or nitrogen, wherein a carbon atom of thering has been substituted for the heteroatom. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopent-3-enyl,cyclohex-3-enyl, tetrahydrofurnayl, pyranyl, pyrrolidinyl, andpiperidinyl. Preferred examples of a “carbocyclic moiety” arecyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[1138] As used herein, the term “heterocycle” or “heterocyclic ring” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 14-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and 1, 2, 3 or 4 heteroatoms independently selected from the groupconsisting of N, O and S and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

[1139] Examples of heterocycles include, but are not limited to,1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl. Preferred 5 to 10 membered heterocycles include, but are notlimited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, andisoquinolinyl. Preferred 5 to 6 membered heterocycles include, but arenot limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 memberedheterocycles include, but are not limited to, pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl,pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring andspiro compounds containing, for example, the above heterocycles.

[1140] As used herein, the term “aryl”, “C₆-C₁₀ aryl” or aromaticresidue, is intended to mean an aromatic moiety containing the specifiednumber of carbon atoms; for example phenyl, pyridinyl or naphthyl.Preferred “aryl” is phenyl. Unless otherwise specified, “aryl” may beunsubstituted or substituted with 0 to 3 groups selected from H, methyl,ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy,Cl, F, Br, I, CF₃, SCH₃, S(O)CH₃, SO₂CH₃, —N(CH₃)₂, N(CH₃)H, CN, NO₂,OCF₃, C(═O)CH₃, CO₂H, CO₂CH₃, or C₁-C₄ haloalkyl.

[1141] As used herein, the term “heteroaryl fused radical” is intendedto denote a 5 or 6 membered aromatic ring comprising carbon atoms andone or two heteroatoms selected from nitrogen, sulphur and oxygen. The 5or 6 membered ring is fused to two adjacent atoms of a second ring, i.e.a bicyclic ring system, wherein the second ring is a “carbocyclicmoiety” as defined above. Examples of a “heteroaryl fused radical” arefuranyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, thiophenyl,thiazolyl, isothiozalyl, pyridyl, pyridazinyl, pyrimidinyl, andpyrazinyl.

[1142] The phrase “additional lactam carbons”, as used herein, isintended to denote the number of optional carbon atoms in the lactamring B of Formula (I). Formula (I′):

[1143] represents the lactam ring B of Formula (I). Additional lactamcarbons are carbons in lactam ring B other than the carbons numbered 2and 3 in the backbone of the formula. The additional lactam carbons maybe optionally replaced by a heteroatom selected from oxygen, nitrogenand sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optionalcarbons, wherein one optional carbon may optionally be replaced by aheteroatom, such that the total number of members of lactam ring B,including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10.It is preferred that the total number of atoms of lactam ring B is 6, 7or 8; it is more preferred that the total number of atoms of lactam ringB is seven. It is further understood that lactam ring B may optionallybe unsaturated or partially unsaturated (i.e. two adjacent atoms in thering form a double bond) wherein the backbone of lactam ring B maycontain one, two or three double bonds. Examples of lactam ring Binclude:

[1144] but are not intended to limit the invention. Preferred examplesof lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; morepreferred examples of lactam ring B are B1, B6, B8, B9, and B13.Preferred examples of substituent R¹⁰ or R¹¹ on lactam B are hydrogen,methyl, ethyl, phenyl, benzyl, phenethyl, 4-fluorophenyl,4-chlorophenyl, 4-methylphenyl, 4-CF₃-phenyl, (4-fluorophenyl)methyl,(4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-CF₃-phenyl)methyl,(4-fluorophenyl)ethyl, (4-chlorophenyl)ethyl, (4-methylphenyl)ethyl,(4-CF₃-phenyl)ethyl, and 2-, 3-, and 4-pyridinyl. More preferredexamples of substituent R¹⁰ or R¹¹ on lactam B are methyl, ethyl,phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-CF₃-phenyl,(4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-CF₃-phenyl)methyl,and 2-, 3-, and 4-pyridinyl. Preferred examples of R¹³ on lactam B areF, Cl, OH, methyl, ethyl, methoxy, and trifluoromethyl.

[1145] It is understood that the functional group of the formula—NH—C(OH)₂— is equivalent to —NH—C(═O)—.

[1146] The compounds herein described may have asymmetric centers. Oneenantiomer of a compound of Formula (I) may display superior biologicalactivity over the opposite enantiomer. For example carbon 3 of lactamring B Formula

[1147] (I″) may exist in either an S or R configuration. Thus, an R or Sconfiguration at carbon 3 in Formula (I″) is considered part of theinvention. An example of such configuration includes, the S isomer:

[1148] but is not intended to be limited to this example of ring B. Whenrequired, separation of the racemic material can be achieved by methodsknown in the art.

[1149] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

[1150] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

[1151] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[1152] “Prodrugs” are intended to include any covalently bonded carrierswhich release the active parent drug according to Formula (I) in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of Formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of Formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of Formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of Formula (I), and the like.

[1153] “Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

SYNTHESIS

[1154] The compounds of the present invention can be prepared in anumber of ways well known to one skilled in the art of organicsynthesis. The compounds of the present invention can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include, butare not limited to, those described below. All references cited hereinare hereby incorporated in their entirety herein by reference.

[1155] The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

[1156] In a preferred method of synthesis, the compounds of Formula (I)of the present invention can be prepared from carboxylic acid 1 andamine 2 using amide bond syntheses known in the art, including methodscommonly used in peptide syntheses, such as HATU, TBTU, BOP, EDC, CDI,and DCC-mediated couplings, as illustrated in Scheme 1. Depending on thestructure of the final product, it is appreciated by those skilled inthe art that protecting groups or precursor functionality convertible tothe desired groups may be desirable. Protecting groups and their use insynthesis are described in Green and Wuts, Protective Groups in OrganicSynthesis, (Wiley 1991).

[1157] Additionally, the syntheses of a representative aminomethylcarboxamide 4a, lactate 7b, and a representative homoaldol 4c of Formula(I) are illustrated in Scheme 2 and Scheme 3, respectively. As will bereadily apparent to those of ordinary skill in the art, the syntheticprocedures illustrated in Scheme 2 and 3, and the reaction conditionsdescribed below can be modified by selecting the appropriate startingmaterials and reagents to allow the preparation of other compounds ofthe present invention.

[1158] Methods for the synthesis of lactams useful as intermediates inthe synthesis of compounds of the present invention, including aminobisbenzodiazepine 5 and amino benzodiazepine 8, are known in the art andare disclosed in a number of references including PCT publication numberWO 98/28268, WO 99/66934, and WO00/07995, which are hereby incorporatedby reference. Additional references include Bock, et. al., J. Org.Chem., 1987, 52, 3232-3239; Sherrill et. al., J. Org. Chem., 1995, 60,730-734; Walsh, D. A., Synthesis, Sep. 1980, p. 677; and Brown, at. al.,Tetrahedron Letters, 1971, 8, 667-670.

[1159] Aminomethyl cyclic carboxylic acid intermediates, such as 4a, areuseful for the synthesis of the current invention, and may besynthesized by a number of ways well known in the art. One of thepreferred syntheses of the compound of this invention is shown in Scheme4. Potassium carbonate-promoted double alkylation reaction of methylester 10 can be employed to give the cyclic ester 11. Thecyanocarboxylic ester 11 is readily reduced to the corresponding amineunder the reaction conditions described by Brown, R. R. et al.,Synthesis, 1982, 1036. The completion of intermediate 4a can be achievedby performing the reductive amination reaction on 12 (J. Org. Chem.,1996, 61, 3849-3862), followed by the hydrolysis of ester 13. It shouldbe apparent to those of ordinary skill in the art that many derivativesof 4a can be prepared in a similar manner from the versatileintermediate 12, upon the selection of an appropriate starting materialand following procedures known in the literature.

[1160] One of the representative syntheses of homoaldol analogs, such as15, is illustrated in Scheme 5. The useful intermediate lactones, suchas 14, are known in the art and one of their syntheses are described inJ. Org. Chem., 1996, 61, 3849-3862.

[1161] One of the preferred syntheses of cyclic lactates, such as 7b,which are useful in the preparation of compounds of Formula (I), isoutlined in Scheme 6. As illustrated for the synthesis of carboxylicacid 7b, intermediate 17 can be prepared by from ester 16, under thereaction conditions which are known in the art and disclosed in a numberof references including J. Org. Chem., 1986, 51, 2402, and Chem. Rev.,1992, 92, 919. Finally, adduct 7b can be prepared by the alkylation of17 and hydrolysis of the resulting ester.

[1162] Depending on the structure of the final product, it isappreciated by those skilled in the art, the synthetic procedureillustrated in Scheme 4, 5, and 6 and the reaction conditions describedwill allow the preparation of many other analogs of 4 and 7 by selectingthe appropriate starting materials and reagents. Many of the startingmaterials employed in this invention are either commercially availableor can be prepared from commercially available materials usingconventional procedures and reagents.

[1163] In order to assist in a further understanding of the currentinvention, one of the representative syntheses of the final inhibitors,such as compound 23, is illustrated in Scheme 7. Target 23 was preparedin 5 steps beginning with starting materials 10 and 18. The initialintermediate 12 was easily prepared under the reaction conditions thatare know in the art (Justus Liebigs Ann. Chem. GE., 639, 1961, 166-180and Helv. Chim. Acta. 1998, 2218-2243). EDC-promoted coupling reactionof the acid 19 and 12 provided the intermediate 20 that was subsequentlyhydrolyzed by LiOH and coupled with the amine 22 to give the finalproduct 23.

[1164] In order to assist in a further understanding of the currentinvention, one of the representative syntheses of the amino alcohol APPinhibitors, such as compound 30, is illustrated in Scheme 8. Molecule 30was prepared in 5 steps. The starting aldehyde 25 was synthesizedaccording to the published procedure of Chem. Lett 1992, 1169-1172. Allother reaction conditions are known in the art. The employed reductiveamination reaction was describe in J. Org. Chem., 1996, 61, 3849.

[1165] Abbreviations used in the description of the chemistry and in theexamples that follow are: Ac acetyl or acetate, aq aqueous, Bn benzyl,Boc tertiary butyloxycarbonyl, BOPbenzotriazol-1-yloxytris-(dimethylamino)- phosphoniumhexafluorophosphate, Cbz benzyloxycarbonyl, DIEAN,N′-diisopropylethylamine, DMAP 4-dimethylaminopyridine, DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, DME ethylene glycoldimethyl ether, DMF N,N′-dimethylformamide, DMSO dimethylsulfoxide ormethyl sulfoxide, EDC · HCl1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate, HOBT 1-hydroxybenzotriazole, HPLC high performanceliquid chromatography, LiHMDS lithium hexamethyldisilazide, MeCNacetonitrile, MS mass spectrometry, satd saturated, rt or RT roomtemperature, TBTU O-(1H-benzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate, TFA trifluoroacetic acid, THF tetrahydrofuran, andTLC thin layer chromatography.

EXAMPLES

[1166] Compounds of the present invention are generally purified by HPLCusing conditions known to one skilled in the art. However, unlessotherwise indicated, the following conditions are generally applicable.

[1167] HPLC Condition A:

[1168] Reverse-phase HPLC can be carried out using a Vydac C-18 columnwith gradient elution from 10% to 100% buffer B in buffer A (buffer A:water containing 0.1% trifluoroacetic acid, buffer B: 10% water, 90%acetonitrile containing 0.1% trifluoroacetic acid).

[1169] HPLC Condition B:

[1170] Alternatively, reverse-phase HPLC can be carried out using aVydac C-18 column with gradient elution from 10% to 90% acetonitrile inwater.

Example 1

[1171]

[1172] (a) ({[(3-methylbutyl)amino]methyl}cyclopentyl)methan-1-ol

[1173] To a solution of methyl1-[N-(3-methylbutyl)-carbamoyl]-cyclopentanecarboxylate (900 mg, 3.7mmol) in THF at rt was added BH₃/THF complex )7.4 mL, 7.4 mmol) andstirred at 75° C. for 5 hours. To this reaction mixture was added 6N HCl(10 mL) and the mixture was further stirred for 30 min before thesolution was neutralized by 1N NaOH. The solution was diluted with waterand extracted with EtOAc. The combined extracts were dried overmagnesium sulfate, and concentrated to a crude oil (700 mg, 95%). MS[M+H]⁺200.

[1174] (b)(tert-butoxy)-N-{[(hydroxymethyl)cyclopentyl]methyl}-N-(3-methylbutyl)carboxamide

[1175] To a solution of({[(3-methylbutyl)amino]methyl}-cyclopentyl)methan-l-ol (700 mg, 3.7mmol) in a 1:1 mixture of CH₂Cl₂/MeOH (20 ml) at 0 ° C. was added NaHCO₃(471 mg, 5.5 mmol) followed by Boc₂O (967 mg, 4.4 mmol). The mixture wasstirred at 0° C. for 30 min then warmed to rt and stirred for 1 hr.About 30 ml of H₂O was added and the mixture was extracted with EtOAc(2×30 mL). The combined extracts were washed with water, dried overMgSO4₁ filtered and concentrated to colorless oil (300mg, 68%). MS[M+H]⁺300.

[1176] (c)1-{[(tert-butoxy)-N-(3-methylbutyl)carbonylamino]-methyl}-cyclopentanecarboxylicacid

[1177] To a solution of(tert-butoxy)-N-{[(hydroxymethyl)-cyclopentyl]methyl}-N-(3-methylbutyl)carboxamide(300 mg, 2.5 mmol) in a 1:1:1 mixture of MeCN/H₂O/CCl₄ (30 ml) at rt wasadded RuCl₃ (10 mg, 0.05 mmol) followed by NaIO₄ (2.2 g, 10.25 mmol).The mixture was stirred at rt for 16 hr, then 30 ml of H₂was added andthe mixture was extracted with CH₂Cl₂ (2×30 mL). The combined extractswere washed with water, dried over MgSO₄, filtered and concentrated to acrude oil (560mg, 71%). MS [M+H]⁺314.

[1178] (d)({[(3-methylbutyl)amino]methyl}cyclopentyl)-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azepin-7-yl))carboxamide

[1179] To a solution of1-{[(tert-butoxy)-N-(3-methylbutyl)-carbonylamino]methyl}-cyclopentanecarboxylicacid (100 mg, 0.3 mmol) in CH₂Cl₂/DMF (5:1, 15 mL) at 0° C. was addedHOBT (50 mg, 0.33 mmol) and EDC (63 mg, 0.33 mmol). The mixture wasstirred for 10 min, then 7-amino-5-methyl-7H-dibenzoazaperhydropin-6-one(obtained as the first eluting peak of the racemic mixture on aCHIRALCEL OD column using 20% iPrOH/Hexane with diethylamine) (68 mg,0.3 mmol) was added and stirring was continued for 1 h. The solution waspoured into water and the layers separated. The aqueous layer wasextracted with methylene chloride and the combined extracts were washedwith water, 1 N HCl, sat'd NaHCO₃, dried over magnesium sulfate, andconcentrated to a glassy solid which was dissolved in methylene chloride(20 mL) and TFA (6 mL) at 0° C. The mixture was stirred for 45 min.,evaporated to dryness, then dissolved in Et₂O (20 mL). To this solutionwas added 1M HCl (in Et₂O) to form the desired HCl salt. The white solidwas collected by filtration, re-dissolved in EtOAc and neutralized using1N NaOH. The solution was diluted with water and extracted with EtOAc.The combined extracts were dried over magnesium sulfate, andconcentrated to a glassy solid (45 mg, 39%). ¹H NMR (300 MHz, CDCl₃)δ7.20-7.58 (m, 8H), 5.38 (d, 1H), 3.45 (s, 3H), 2.80 (s, 2H), 2.75 (m,2H), 1.4-2.30 (m, 11H), 0.8 (d, 6H). MS [M+H]⁺434.

Example 2

[1180]

[1181] The title compound was prepared in a manner similar to thatdescribed for Example 1. The product was obtained as a colorless oil. ¹HNMR (300 MHz, CDCl₃) δ7.20-7.58 (m, 8H), 5.38 (d, 1H), 4.20 (m, 2H),3.60 (m, 2H), 3.40 (s, 3H), 3.00 (m, 1H), 1.20-2.20 (m, 14H), 0.8 (d,6H). MS [M+H]⁺506.

Example 3

[1182]

[1183] The title compound was prepared in a manner similar to thatdescribed for Example 1. This compound was made from the correspondingamino benzodiazepine that, as the Cbz protected form, was the firsteluting peak of the racemic mixture on a CHIRALPAK AD column usingacetonitrile. The product was obtained as a colorless oil. ¹H NMR (300MHz, CDCl₃) δ7.20-7.80 (m, 8H), 5.60 (d, 1H), 3.45 (s, 3H), 2.80 (s,2H), 2.75 (m, 2H), 1.4-2.20 (m, 1H), 0.90 (m, 6H). MS [M+H]⁺529.

Example 4

[1184]

[1185] The title compound was prepared in a manner similar to thatdescribed for Example 1 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300MHz,CDCl₃) δ6 7.64-7.32 (m, 8H), 5.41 (d, 1H), 3.88-3.70 (m, 4H), 3.36 (s,3H), 2.88-2.75 (m, 4H), 1.80-1.48 (m, 7H), 0.94 (d, 6H). MS [M+H]⁺450.

Example 5

[1186]

[1187] (a) Methyl 1-(5-methylhexyl)cyclopentanecarboxylate

[1188] To a solution of methyl cyclopentanecarboxylate (300 mg, 2.3mmol) in THF (20 ml) at −78° C. was added LHMDS (4.6 mL, 4.6 mmol) andstirred for 30 min, and followed by 1-bromo-5-methylhexane (626 mg, 3.5mmol). The mixture was stirred from −78° C. to rt over 16 hr, before 30ml of H₂O was added and then was extracted with CH₂Cl₂ (2×30 mL). Thecombined extracts were washed with water, dried over MgSO₄, filtered andconcentrated, then purified using flash chromatography to give an oil(110 mg, 21%). MS [M+H]⁺333.

[1189] (b) 1-(5-Methylhexyl)cyclopentanecarboxylic acid

[1190] To a solution of methyl 1-(5-methyl-hexyl)cyclopentanecarboxylate(110 mg, 0.4 mmol) in 21 mL of THF cooled to 0° C. was added dropwise asolution of lithium hydroxide monohydrate (26 mg, 0.6 mmol) in 5.0 mL ofwater. The reaction mixture was stirred at rt for 16 h. THF was removedunder reduced pressure to give a yellow oil which was diluted with 10 mLof 1 N HCl. The aqueous phase was extracted with CH₂Cl₂ (8×15 mL), andthe extracts were combined, dried over Na₂SO₄, and concentrated toafford 60 mg (71%) of the desired product. MS [M+H]⁺213.

[1191] (c)[(5-methylhexyl)cyclopentyl]-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide

[1192] To a solution of 1-(5-methylhexyl)cyclopentane-carboxylic acid(20 mg, 0.09 mmol) in CH₂Cl₂/DMF (5:1, 15 mL) at 0° C. was added HOBT(15 mg, 0.1 mmol) and EDC (19 mg, 0.1 mmol). The mixture was stirred for10 min then (S)-3-amino-1-methyl-5-phenyl-3H-benzo[f]1,4-diazepin-2-one(48 mg, 0.1 mmol) was added and stirring was continued for 1 h. Thesolution was poured into water and the layers separated. The aqueouslayer was extracted with methylene chloride and the combined extractswere washed with water, 1N HCl, sat'd NaHCO₃, dried over magnesiumsulfate, concentrated, and purified using flash chromatography to give awhite solid (25 mg, 66%). ¹H NMR (300 MHz, CDCl₃) δ7.15-7.58 (m, 9H),5.48 (d, 1H), 3.40 (s, 3H), 2.80 (m, 2H), 1.22-2.70 (m, 14H), 0.8 (d,6H). MS [M+H]⁺460.

Example 6

[1193]

[1194] The title compound was prepared in a manner similar to thatdescribed for Example 5. The product was obtained as a colorless oil. 1HNMR (300MHz, CDCl₃) δ7.62−7.20 (m, 9H), 5.58 (d, 1H), 3.47 (s, 3H),2.28−2.15 (m, 2H), 1.78−1.12 (m, 14H), 0.91 (t, 3H). MS [M+H]⁺432.

Example 7

[1195]

[1196] The title compound was prepared in a manner similar to thereaction described in J. Org. Chem. 1994, 59, 520 and described forExample 1. The product was obtained as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ0.90 (t, J=7 Hz, 3H), 1.25-1.70 (mbr, 15H), 1.78-1.90 (m, 1H),2.10-2.26 (br, 2H), 3.45 (s, 3H), 3.82-3.93 (m, 1H), 5.60 (d, J=8 Hz,1H), 7.21-7.28 (m, 1H), 7.35-7.42 (m, 4H), 7.45-7.50 (m, 1H), 7.58-7.65(m, 3H), 7.73 (d, J=8 Hz, 1H). MS [M+H]⁺462.

Example 8

[1197]

[1198] The title compound was prepared in a manner similar to thatdescribed for Example 7 from the appropriate intermediates. The productwas obtained as a colorless oil. MS [M+H]⁺448.

Example 9

[1199]

[1200] The title compound was prepared in a manner similar to thatdescribed for Example 1 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ7.20-7.58 (m, 9H), 6.60-6.80 (m, 4H), 5.38 (d, 1H), 3.80-4.0 (m,4H), 3.50 (s, 2H), 2.40 (s, 3H), 2.15 (m, 2H), 1.70 (m, 4H). MS[M+H]⁺534.

Example 10

[1201]

[1202] (a) methyl 1-cyanocyclopentanecarboxylate

[1203] A solution of methyl 2-cyanoacetate (30 mL, 340 mmol) in DMF (26mL) and DBU (112 mL, 748 mmol) was heated to 50° C. for 15 min and thencooled to −20° C. To this stirred solution was added dibromobutane 18.The internal temperature increased to 70° C. during the addition. Thereaction was set aside to cool to rt before quenching with H₂O (800 mL).The product was extracted with Et₂O (3×300 mL). The ether layer waswashed with 1N HCl (400 mL) and H₂O (400 mL). The combined extracts weredried over magnesium sulfate, and concentrated to a crude oil that wasdistilled under high vacuum at 80° C. to yield the desired product in58% yield.

[1204] (b) methyl 1-(aminomethyl)cyclopentanecarboxylate

[1205] To a solution of methyl 1-cyanocyclopentanecarboxylate (15 g, 98mmol) in MeOH (250 mL) was added RaNi (3 g). The reaction was chargedwith H₂ at 50 psi and shaken in the Parr shaker for 24 h. The RaNicatalyst was removed by filtration through a layer of celite. Thesolvent was removed under vacuum. The crude product was dissolved in 1NNaHSO₄ (100 mL) and then washed with Et₂O (2×100 mL). The organic layerwas dried over magnesium sulfate and then filtered. The solvents wereremoved under reduced pressure to provide the amine in 77%; ¹H NMR (300MHz, CD3OD) δ3.75 (s, 3H), 3.12 (s, 2H), 2.14×2.07 (m, 2H), 1.83×1.65(m, 6H). MS [M+H]⁺470.

[1206] (c) methyl 1-[(2-(S)-hydroxy-3-methylbutanoylamino)methyl]cyclopentanecarboxylate

[1207] To a solution of (S)-2-hydroxy-3-methyl-butyric acid (300 mg, 2.5mmol) in CH₂Cl₂/DMF (5:1, 20 mL) at 0° C. was added HOBT (382 mg, 2.5mmol) and EDC (477 mg, 2.5 mmol). The mixture was stirred for 10 minthen methyl 1-(aminomethyl)cyclopentanecarboxylate (321 mg, 2.25 mmol)and iPr₂NEt (0.5 mL, 2.5 mmol) were added and stirring was continued for3 h. The reaction was diluted with water and extracted with EtOAc. Thecombined extracts were washed with water, 1N HCl, sat'd NaHCO₃, driedover magnesium sulfate, concentrated, and purified using flashchromatography to give a white solid (420 mg, 72%). MS [M+H]⁺258.

[1208] (d)1-[(2-(S)-hydroxy-3-methylbutanoylamino)methyl]-cyclopentanecarboxylicacid

[1209] To a solution of methyl1-[(2-(S)-hydroxy-3-methylbutanoylamino)methyl] cyclopentane carboxylate(170 mg, 0.66 mmol) in 21 mL of THF cooled to 0° C. was added dropwise asolution of lithium hydroxide monohydrate (110 mg, 2.6 mmol) in 5.0 mLof water. The reaction mixture was stirred at rt for 6 h. THF wasremoved under reduced pressure to give a yellow oil which was dilutedwith 10 mL of 1 N HCl. The aqueous phase was extracted with CH₂Cl₂(2×15mL), and the extracts were combined, dried over Na₂SO₄, and concentratedto afford 105 mg (65%) of the desired product. MS [M +H]⁺244.

[1210] (e)2-(S)-hydroxy-3-methyl-N-{[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl) cyclopentyl]methyl} butanamide

[1211] To a solution of 1-[(2-(S)-hydroxy-3-methylbutanoylamino)methyl]cyclopentanecarboxylic acid (110 mg, 0.45 mmol) in CH₂Cl₂/DMF (5:1, 15mL) at rt was added HOBT (75 mg, 0.49 mmol) and EDC (95 mg, 0.49 mmol).The mixture was stirred for 10 min then(S)-3-amino-1-methyl-5-[4-(trifluoromethyl)phenyl]-3H-benzo[f]1,4-diazepin-2-onehydrogen bromide salt (186 mg, 0.45 mmol) and iPr₂NEt (0.1 mL, 0.49mmol) were added and stirring was continued for 16 h. (The aminobenzodiazepine was obtained as described in Example 3.) The reaction wasdiluted with water, extracted with EtOAc and the combined extracts werewashed with water, 1 N HCl, sat'd NaHCO₃, dried over magnesium sulfate,concentrated on the rotavapor, and purified on the flash chromatographyto give a white solid (120 mg, 48%). ¹H NMR (300 MHz, CDCl₃) δ7.20-7.80(m, 8H), 6.60-6.80 (m, 4H), 5.48 (d, 1H), 4.00 (d, 1H), 3.40-3.60 (m,2H), 3.50 (s, 3H), 1.60-2.20 (m, 9H) 1.00 (d, 3H), 0.9 (d, 3H); MS [M+H]⁺559.

Example 11

[1212]

[1213] The title compound was prepared in a manner similar to thatdescribed for Example 9 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ7.20-7.80 (m, 8H), 6.60-6.80 (m, 4H), 5.20 (d, 1H), 3.80 (d,1H), 3.40 (d, 2H), 3.30 (s, 3H), 1.60-2.20 (m, 9H) 1.00 (d, 3H), 0.80(d, 3H); MS [M+H]⁺464.

Example 12

[1214]

[1215] The title compound was prepared in a manner similar to thatdescribed for Example 9 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ7.20-7.80 (m, 8H), 5.20 (d, 1H), 4.00 (m, 1H), 3.40 (m, 2H),3.30 (s, 3H), 1.40-2.20 (m, 11H), 0.80 (m, 6H); MS [M+H]⁺478.

Example 13

[1216]

[1217] The title compound was prepared in a manner similar to thatdescribed for Example 9 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300MHz,CDCl₃) δ7.65−7.15 (m, 9H), 6.80−6.60 (m, 4H), 5.25 (d, 1H), 3.43−3.36(m, 7H), 2.15×1.70 (m, 8H). MS [M+H]⁺518.

Example 14

[1218]

[1219] The title compound was prepared in a manner similar to thatdescribed for Example 9. The product was obtained as a colorless oil. ¹HNMR (300MHz, CDCl₃) δ7.60−7.26 (m, 9H), 7.20 (m, 1H), 7.02 (m, 1H), 5.47(d, 1H), 3.92 (d, 1H), 3.60−3.38 (m, 5H), 2.18−1.62 (m, 9H), 0.97 (d,3H), 0.82 (d, 3H). MS [M +H]⁺509.

Example 15

[1220]

[1221] The title compound was prepared in a manner similar to thatdescribed for Example 9. The product was obtained as a colorless oil. ¹HNMR (300MHz, CDCl₃) δ7.58−7.46 (m, 2H), 7.36−7.24 (m, 2H), 5.31 (d, 1H),3.97 (m, 1H), 3.76- 3.26 (m, 6H), 2.20−1.10 (m, 17H), 1.00 (d, 3H), 0.85(d, 3H) . MS [M+H]⁺483.

Example 16

[1222]

[1223] The title compound was prepared in a manner similar to thatdescribed for Example 1 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300MHz,CDCl₃) δ7.56−7.22 (m, 8H), 5.24 (d, 1H), 3.29 (s, 3H), 2.64−1.54 (m,15H), 0.80 (d, 6H). MS [M+H]⁺434.

Example 17

[1224]

[1225] The title compound was prepared in a manner similar to thatdescribed for Example 1 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ7.52−7.20 (m, 8H), 5.22 (d, 1H), 3.25 (s, 3H), 2.58 (m, 2H),2.36 (d, 2H), 2.10 (m, 2H), 1.82 (m, 2H), 1.70−1.50 (m, 6H), 0.91 (m,1H), 0.36 (m, 2H), 0.01 (m, 2H). MS [M+H]⁺432.

Example 18

[1226]

[1227] The title compound was prepared in a manner similar to thatdescribed for Example 1 using the amino bisbenzazepine employed inExample 1. ¹H NMR (300MHz, CDCl₃) δ7.61−7.28 (m, 8H), 6.83−6.61 (m, 3H),5.37 (d, 1H), 3.36 (s, 3H), 3.06−2.88 (m, 6H), 2.20−1.42 (m, 8H). MS[M+H]⁺504.

Example 19

[1228]

[1229] The title compound was prepared in a manner similar to thatdescribed for Example 1 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300MHz,CDCl₃) δ7.61−7.20 (m, 8H), 7.07−7.00 (m, 2H), 6.70 (m, 1H), 5.37 (d,1H), 3.99−3.85 (q, 2H), 3.37 (s, 3H), 2.87−2.80 (q, 2H), 2.20−1.52 (m,8H). MS [M+H]⁺490.

Example 20

[1230]

[1231] The title compound was prepared in a manner similar to thatdescribed for Example 1 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300MHz,CDCl₃) δ7.60−7.30 (m, 8H), 5.37 (d, 1H), 3.35 (s, 3H), 2.92−2.79 (m,4H), 2.22−1.02 (m, 19H). MS [M+H]⁺460.

Example 21

[1232]

[1233] The title compound was prepared in a manner similar to thatdescribed for Example 1. The product was obtained as a white solid (173mg, 75%): mp=82-86° C.; ¹H NMR (500 MHz, CD₃OD) δ7.71 (t, J=2.3 Hz, 1H), 7.69−7.31 (m, 8 H), 5.36 (s, 1 H), 3.48 (s, 3 H), 2.87 (m, 2 H),2.52 (m, 1 H), 2.15−2.01 (m, 4 H), 1.78−1.59 (m, 10 H), 1.32−1.20 (m, 4H); IR (CH₂Cl₂) 2928, 2853, 2360, 1689, 1658, 1520, 1448, 698 cm⁻¹; ESIMS m/z=473 [C₂₉H₃₆N₄O₂+H]+; HPLC>95%, t_(r)=19.92 min; Anal. Calcd. forC₂₉H₃₆N₄O₂-0.25H₂O; C, 72.99; H, 7.72; N, 11.75. Found: C, 72.80; H,7.68; N, 11.47 colorless oil. MS [M+H]⁺460.

Example 22

[1234]

[1235] (a) 27 (Scheme 8).

[1236] To a stirred solution of aldehyde 25 (1.2 g, 5.6 mmol) in CH₂Cl₂(20 ml) at 25° C. was added amine 26 (1 g, 5.6 mmol). After 30 min.NaHB(OAc)₃ (3.5 g, 16.8 mmol) was added. The mixture was stirred at rtfor 16 hr, then 30 ml of H₂O was added and the mixture was extractedwith CH₂Cl₂ (2×30 mL). The combined extracts were washed with water,dried over MgSO₄, filtered and concentrated, then purified using flashchromatography to give a clear oil (1 g, 53%). MS [M+H]⁺333.

[1237] (b) 28 (Scheme 8).

[1238] To a solution of 27 (1 g, 2.8 mmol) in 21 mL of THF cooled to 0°C. was added dropwise a solution of lithium hydroxide monohydrate (588mg, 14 mmol) in 5.0 mL of water. The reaction mixture was stirred at rtfor 16 h. THF was removed under reduced pressure to give a yellow oilwhich was diluted with 10 mL of 1 N HCl. The aqueous phase was extractedwith CH₂Cl₂ (8×15 mL), and the extracts were combined, dried overNa₂SO₄, and concentrated to afford 750 mg (78%) of the desired product.MS [M+H]⁺213.

[1239] (c) 29 (Scheme 8).

[1240] To a solution of the acid 28 (240 mg, 0.69 mmol) in DMF (15 mL)at 0° C. was added HATU (288 mg, 0.76 mmol). The mixture was stirred for10 min and then 7-amino-5-methyl-7H-dibenzoazaperhydropin-6-one (160 mg,0.69 mmol) was added followed by iPrNEt₂ (0.14 mL, 0.76 mmol andstirring was continued for 16 h. (The amino bisbenzazepine was obtainedas the first eluting peak of the racemic mixture on a CHIRALCEL ODcolumn using 20% iPrOH/Hexane with diethylamine). The solution waspoured into water and the layers separated. The aqueous layer wasextracted with EtOAc and the combined extracts were washed with water,IN HC₁, sat'd NaHCO₃, dried over magnesium sulfate, concentrated, thenpurified using flash chromatography to give an oil (300 mg, 77%). MS[M+H]⁺433.

[1241] (d) 30 (Scheme 8).

[1242] To a solution of 29 (300 mg, 0.53 mmol) in THF (20 ml) at 25° C.was added TBAF (2.7 mL, 2.66 mmol). The mixture was stirred at rt for 16hr, then 30 ml of H₂O was added and the mixture was extracted withCH₂Cl₂ (2×30 mL). The combined extracts were washed with water, driedover MgSO₄, filtered and concentrated, then purified using flashchromatography to give a clear oil (150 mg, 63%). ¹H NMR (300 MHz,CDCl₃) δ7.30-7.60 (m, 8H), 5.40 (d, 1H), 3.90 (m, 1H), 3.20 (s, 3H),2.60 (m, 2H), 1.60-2.20 (m, 9H) 1.50 (m, 1H), 1.20 (m, 1H), 0.80 (m,6H); MS [M+H]⁺450.

Example 23

[1243]

[1244] The title compound was prepared in a manner similar to thatdescribed for Example 21 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ7.30-7.60 (m, 8H), 5.40 (d, 1H), 3.60 (m, 1H), 3.40 (s, 3H),2.60 (m, 2H), 1.60-2.20 (m, 11H) 1.05 (d, 3H), 0.90 (d, 3H); MS[M+H]+436.

Example 24

[1245]

[1246] The title compound was prepared in a manner similar to thatdescribed for Example 21 using the amino bisbenzazepine employed inExample 1. The product was obtained as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ7.30-7.60 (m, 8H), 5.40 (d, 1H), 3.60 (m, 1H), 3.40 (s, 3H),2.60 (m, 2H), 1.00-2.20 (m, 19H); MS [M+H]⁺476.

Example 25

[1247]

[1248] The title compound was prepared using the method as describedbelow.

[1249] Preparation of Intermediate 33

[1250] To a stirred solution of acid 32 (397 mg, 1.6 mmol) was addedHOBt (226 mg, 1.7 mmol), EDC (312 mg, 1.6 mmol) and DIPEA (1.0 mL, 5.9mmol). The reaction was stirred 15 min and benzodiazepine 31, (seeExample 3), was added in one portion and the reaction stirred overnight.Water was added and the layers separated. The organic layer was washedwith 5% sodium bicarbonate and brine. The organic solution was driedover magnesium sulfate, filtered and concentrated. The residue waschromatographed in 50% ethyl acetate in hexanes to provide 33 as an oil.The oil was dissolved in ether. Hexanes were added and the mixtureevaporated to provide 33 (736 mg, 88%) as a white solid: ¹H NMR (300MHz, CDCl₃) δ6 7.71 (d, 2 H), 7.67 (d, 2 H), 7.61 (m, 1 H), 7.41 (d, 1H), 7.3−7.2 (m, 3 H) 5.53 (m, 1 H), 5.51 (d, 1 H), 3.48 (s, 3 H), 3.31(t, 2 H), 2.11−1.99 (m, 2 H), 1.78 (m, 6 H), 1.45 (s, 9 H).

[1251] Preparation of Intermediate 34

[1252] To a stirred solution of 33 (730 mg, 1.3 mmol) in methylenechloride (10 mL) was added trifluoroacetic acid (10 mL) and the reactionstirred 4 h. The reaction was evaporated and chromatographed over silicagel with a 1:1 mixture of ethyl acetate and 6:3:1 chloroform, methanol,and ammonium hydroxide. The eluent was concentrated and methanol added.The solution was evaporated and chromatographed in a 1:1 mixture ofethyl acetate and 6:3:1 chloroform, methanol, and ammonium hydroxide toprovide 34 (550 mg, 91%) as a white solid: ¹H NMR (CDCl₃) δ9.17 (d, 1H), 7.73 (d, 2 H), 7.62 (d,2 H), 7.62−7.52 (m, 1 H), 7.36 (d, 1 H),7.33−7.17 (m, 2 H), 5.58 (d, 1 H), 3.50 (s, 3 H), 2.98 (s, 2 H),2.26−2.10 (m, 2 H), 1.88−1.48 (m, 8 H).

[1253] Preparation of Example 25

[1254] To a stirred solution of 34 (70 mg, 0.15 mmol) in isopropanol(0.5 mL) was added 1,2 epoxyhexane (18 μL, 0.15 mmol) and the reactionvial capped and heated at 80° C. for 12 h. Additional 1,2 epoxyhexane(˜40 μL) was added and the reaction heated an additional 18 h. Thereaction was concentrated and chromatographed over silica gel in ethylacetate to provide the title compound Example 25 (54 mg, 63%) as a whitesolid: mp 61-70° C.; ¹H NMR (300 MHz, CDCl₃) δ10.38 (dd, 1 H), 7.75 (d,2 H), 7.65 (d, 2 H), 7.65−7.55 (m, 1 H), 7.39 (d, 1 H), 7.30−7.20 (m, 2H), 5.55 (d, 1 H), 3.92 (m, 1 H), 3.70 (m, 1 H), 3.48 (s, 3 H),2.93−2.73 (m, 3 H), 2.60 (t, 1 H), 2.30−2.03 (m, 2 H), 1.83−1.20 (m, 12H), 0.88 (m, 4 H); IR (KBr) 3432, 2955, 1662, 1522, 1324, 1129, 1067cm⁻¹; ESI MS m/z=559 [C₃₀H₃₇F₃N₄O₃+H]+; HPLC>95%, t_(r)=18.81 min. usingHPLC condition A.

Example 26

[1255]

[1256] The title compound was prepared using the method similar to thatdescribed for Example 25. The product was obtained as a white solid (20mg, 23%): mp 82-86° C.; ¹H NMR (300 MHz, CDCl₃) δ10.30 (d, 1 H), 7.73(d, 2 H), 7.63 (d, 2 H), 7.63-7.53 (m, 1 H), 7.36 (d, 2 H), 7.35-7.20(m, 8 H), 5.60 (d, 1 H), 4.90 (d, 1 H), 4.45 (broad s, 1 H), 3.50 (s, 3H), 3.0−2.8 (m, 4 H), 2.3−2.1 (m, 2 H), 1.84−1.45 (m, 5 H); IR (neat)3424, 2951, 1658, 1518, 1323, 1127 cm⁻¹; ESI MS m/z=579[C₃₂H₃₃F₃N₄O₃+H]+; HPLC>95%, t_(r)=20.11 min. using HPLC condition A.

Example 27

[1257]

[1258] The title compound was prepared using the method similar to thatdescribed for Example 25. The product was obtained as a white solid (35mg, 40%): mp 86-90° C., ¹H NMR (300 MHz, CDCl₃) δ6 10.2 (s, 1 H), 7.73(d, 2 H), 7.60 (d, 2 H), 7.65-7.59 (m, 1 H), 7.40 (d, 1 H), 7.35 (t, 1H), 7.25−7.18 (6 H), 5.58 (d, 1 H), 4.92 (d, 1 H), 4.5 (broad s, 1 H),3.5 (s, 3 H), 3.0−2.8 (m, 4 H), 2.3−2.1 (m, 2 H), 1.9−1.4 (m, 9 H); IR(KBr) 3424, 2952, 1663, 1324, 1127 cm⁻¹; ESI MS m/z=579[C₃₂H₃₃F₃N₄O₃+H]⁺; HPLC>95%, t_(r)=18.73 min. using HPLC condition A.

Example 28

[1259]

[1260] The title compound was prepared in a manner similar to thatdescribed for Example 22 using the amino benzodiazepine employed inExample 3. The product was obtained as oil. ¹H NMR (300 MHz, CD₃OD) δ67.20-7.80 (m, 8H), 5.45 (m, 1H), 3.45 (s, 3H), 2.20 (m, 3H), 2.00−1.60(m, 5H). MS [M+H]+445.

[1261] Tables 1-4 below provide representative Examples of the compoundsof Formula (I) of the present invention. TABLE 1

Ex. # Q CR⁵R^(5a) -WXYZ 1 [(3-Me-butyl)amino]-methyl cyclopentyl Me 2[N′-(ethoxycarbonyl)-N′-(3-Me-butyl)amino]-methyl cyclopentyl Me 4[(3-Me-butyl)amino]-methyl perhydro-2H-pyran Me 8 2-hydroxy-pentylcyclopentyl Me 9 [(3,5-diF-benzyl)C(═O)NH]-methyl perhydro-2H-pyran Me11 [(1-hydroxy-2-Me-propyl)C(═O)NH]-methyl cyclopentyl Me 12[(1-hydroxy-3-Me-butyl)C(═O)NH]-methyl cyclopentyl Me 13[(3,5-diF-benzyl)C(═O)NH]-methyl cyclopentyl Me 162-[(2-Me-propyl)amino]-ethyl cyclopentyl Me 172-[(cyclopropylmethyl)amino]-ethyl cyclopentyl Me 18[(3,5-diF-phenethyl)amino]-methyl cyclopentyl Me 19[(1,4-diF-benzyl)amino]-methyl cyclopentyl Me 20[(2-cyclopentylethyl)amino]-methyl cyclopentyl Me 22(2-hydroxy-4-Me-pentyl)amino cyclopentyl Me 23(2-hydroxy-3-Me-butyl)amino cyclopentyl Me 24(2-cyclohexyl-2-hydroxy-ethyl)amino cyclopentyl Me

[1262] TABLE 2

Ex. # Q CR⁵R^(5a) -WXYZ R¹¹  3 [(3-Me-butyl)amino]-methyl cyclopentyl Me4-CF₃-phenyl  5 5-Me-hexyl cyclopentyl Me phenyl  6 n-pentyl cyclopentylMe phenyl  7 2-hydroxy-pentyl cyclohexyl Me phenyl 10[(1-hydroxy-2-Me-propyl)-C(═O)NH]-methyl cyclopentyl Me 4-CF₃-phenyl 15[(1-hydroxy-2-Me-propyl)-C(═O)NH]-methyl cyclopentyl Me cyclopentyl 21(cyclohexylamino)-methyl cyclopentyl Me phenyl 25[(2-hydroxy-hexyl)amino]-methyl cyclohexyl Me 4-CF₃-phenyl 26*[(2-hydroxy-2-phenyl)-ethylamino]-methyl cyclohexyl Me 4-CF₃-phenyl 27*[(2-hydroxy-2-phenyl)-ethylamino]-methyl cyclohexyl Me 4-CF₃-phenyl

[1263] TABLE 3

Ex. # Q CR⁵R^(5a) R¹¹ R¹³ 14 [(1-hy- cyclo- phen- Fdroxy-2-Me-propyl)-C(═O)NH]-methyl pentyl yl

UTILITY

[1264] Aβ production has been implicated in the pathology of Alzheimer'sDisease (AD). The compounds of the present invention have utility forthe prevention and treatment of AD by inhibiting Aβ production. Methodsof treatment target formation of Aβ production through the enzymesinvolved in the proteolytic processing of β amyloid precursor protein.Compounds that inhibit β or γsecretase activity, either directly orindirectly, control the production of Aβ. Such inhibition of β orγsecretases reduces production of Aβ, and is expected to reduce orprevent the neurological disorders associated with Aβ protein, such asAlzheimer's Disease.

[1265] Cellular screening methods for inhibitors of Aβ production,testing methods for the in vivo suppression of Aβ production, and assaysfor the detection of secretase activity are known in the art and havebeen disclosed in numerous publications, including J.Med.Chem. 1999, 42,3889-3898; PCT publication number WO 98/22493, EPO publication number0652009; U.S. Pat. No. 5,703,129; and U.S. Pat. No. 5,593,846; allhereby incorporated by reference.

[1266] The compounds of the present invention have utility for theprevention and treatment of disorders involving Aβ production, such ascerebrovascular disorders.

[1267] Compounds of Formula (I) are expected to possess γ-secretaseinhibitory activity. The β-secretase inhibitory activity of thecompounds of the present invention is demonstrated using assays for suchactivity, for example, using the assay described below. Compounds of thepresent invention have been shown to inhibit the activity ofβ-secretase, as determined by the Aβ immunoprecipitation assay.

[1268] Compounds provided by this invention should also be useful asstandards and reagents in determining the ability of a potentialpharmaceutical to inhibit Aβ production. These would be provided incommercial kits comprising a compound of this invention.

[1269] As used herein “μg” denotes microgram, “mg” denotes milligram,“g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS”denotes sodium dodecyl sulfate, and “DMSO” denotes dimethyl sulfoxide,and “EDTA” denotes ethylenediaminetetraacetato.

[1270] A compound is considered to be active if it has an IC₅₀ or K_(i)value of less than about 100 μM for the inhibition of Aβ production.Preferrably the IC₅₀ or K_(i) value is less than about 10 μM; morepreferrably the IC₅₀ or K_(i) value is less than about 0.1 μM. Thepresent invention has been shown to inhibit Aβ protein production withan IC₅₀ or K_(i) value of less than 100 μM.

[1271] β Amyloid Precursor Protein Accumulation Assay

[1272] A novel assay to evaluate the accumulation of Aβ protein wasdeveloped to detect potential inhibitors of secretase. The assay usesthe N 9 cell line, characterized for expression of exogenous APP byimmunoblotting and immunoprecipitation.

[1273] The effect of test compounds on the accumulation of Aβ in theconditioned medium is tested by immunoprecipitation. Briefly, N 9 cellsare grown to confluency in 6-well plates and washed twice with 1×Hank'sbuffered salt solution. The cells are starved in methionine/cysteinedeficient media for 30 min, followed by replacement with fresh deficientmedia containing 150uCi S35 Translabel (Amersham). Test compoundsdissolved in DMSO (final concentration 1%) are added together with theaddition of radiolabel. The cells are incubated for 4 h at 37° C. in atissue culture incubator.

[1274] At the end of the incubation period, the conditioned medium isharvested and pre-cleared by the addition of 5 μl normal mouse serum and50 μl of protein A Sepharose (Pharmacia), mixed by end-over-end rotationfor 30 minutes at 4° C., followed by a brief centrifugation in amicrofuge. The supernatant is then harvested and transferred to freshtubes containing 5 μg of a monoclonal antibody (clone 1101.1; directedagainst an internal peptide sequence in Aβ) and 50 μl protein ASepharose. After incubation overnight at 4° C., the samples are washedthree times with high salt washing buffer (50 mM Tris, pH 7.5, 5 500 mMNaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with low salt washbuffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40),and three times with 10 mM Tris, pH 7.5. The pellet after the last washis resuspended in SDS sample buffer (Laemmli, 1970) and boiled for 3minutes. The supernatant is then fractionated on either 10-20%Tris/Tricine SDS gels or on 16.5% Tris/Tricine SDS gels. The gels aredried and exposed to X-ray film or analyzed by phosphorimaging. Theresulting image is analyzed for the presence of Aβ polypeptides. Thesteady-state level of Aβ in the presence of a test compound is comparedto wells treated with DMSO (1%) alone. A typical test compound blocks Aβaccumulation in the conditioned medium, and is therefore consideredactive, with an IC₅₀ less than 100 μM.

[1275] C-Terminus β Amyloid Precursor Protein Accumulation Assay Theeffect of test compounds on the accumulation of C-terminal fragments isdetermined by immunoprecipitation of APP and fragments thereof from celllysates. N 9 cells are metabolically labeled as above in the presence orabsence of test compounds. At the end of the incubation period, theconditioned medium are harvested and cells lysed in RIPA buffer (10 mMTris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate, 0.1% SDS,150mM NaCl, 0.125% NaN₃). Again, lysates are precleared with 5 μl normalrabbit serum/50 μl protein A Sepharose, followed by the addition of BC-1antiserum (15 μl;) and 50 μl protein A Sepharose for 16 hours at 4° C.The immunoprecipitates are washed as above, bound proteins eluted byboiling in SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE.After exposure to X-ray film or phosphorimager, the resulting images areanalyzed for the presence of C-terminal APP fragments. The steady-statelevel of C-terminal APP fragments is compared to wells treated with DMSO(1%) alone. A typical test compound stimulates C-terminal fragmentaccumulation in the cell lysates, and is therefore considered active,with an IC₅₀ less than 100 μM.

[1276] Aβ Immunoprecipitation Assay

[1277] This immunoprecipitation assay is specific for γ secretase (i.e.,proteolytic activity required to generate the C-terminal end of Aβeither by direct cleavage or generating a C-terminal extended specieswhich is subsequently further proteolyzed). N 9 cells are pulse labeledin the presence of a reported γ secretase inhibitor (MDL 28170) for 1 h,followed by washing to remove radiolabel and MDL 28170. The media isreplaced and test compounds are added. The cells are chased forincreasing periods of times and A β is isolated from the conditionedmedium and C-terminal fragments from cell lysates (see above). The testcompounds are characterized whether a stabilization of C-terminalfragments is observed and whether Aβ is generated from these accumulatedprecursor. A typical test compound prevents the generation of Aβ out ofaccumulated C-terminal fragments and is considered active with an IC₅₀less than 100 μM.

Dosage and Formulation

[1278] The compounds of the present invention can be administered orallyusing any pharmaceutically acceptable dosage form known in the art forsuch administration. The active ingredient can be supplied in soliddosage forms such as dry powders, granules, tablets or capsules, or inliquid dosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

[1279] The compounds of the present invention can be administered insuch oral dosage forms as tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixirs, tinctures, suspensions, syrups, and emulsions.Likewise, they may also be administered in intravenous (bolus orinfusion), intraperitoneal, subcutaneous, or intramuscular form, allusing dosage forms well known to those of ordinary skill in thepharmaceutical arts. An effective but non-toxic amount of the compounddesired can be employed to prevent or treat neurological disordersrelated to β-amyloid production or accumulation, such as Alzheimer'sdisease and Down's Syndrome.

[1280] The compounds of this invention can be administered by any meansthat produces contact of the active agent with the agent's site ofaction in the body of a host, such as a human or a mammal. They can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butgenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

[1281] The dosage regimen for the compounds of the present inventionwill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient,and the effect desired. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter, or arrest the progress of thecondition.

[1282] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

[1283] The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

[1284] In the methods of the present invention, the compounds hereindescribed in detail can form the active ingredient, and are typicallyadministered in admixture with suitable pharmaceutical diluents,excipients, or carriers (collectively referred to herein as carriermaterials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, elixirs, syrups and thelike, and consistent with conventional pharmaceutical practices.

[1285] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

[1286] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamallar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

[1287] Compounds of the present invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

[1288] Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance. In general, water, a suitable oil, saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, buffer substances. Antioxidizingagents such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or combined, are suitable stabilizing agents. Also used arecitric acid and its salts and sodium EDTA. In addition, parenteralsolutions can contain preservatives, such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

[1289] Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof,wherein: Q is —(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(m)—CH (OH)—R⁴,—(CR⁷R^(7a))_(m)—NHC(═O)—R⁴, —(CR⁷R^(7a))_(n)—S—R⁴,—(CR⁷R^(7a))_(n)—O—R⁴, —(CR⁷R^(7a))_(n)—O—N(R^(7b))—R⁴,—(CR⁷R^(7a))_(n)S(═O)—R⁴, —(CR⁷R^(7a))_(n)—S(═O)₂—R⁴, or—(CR⁷R^(7a))_(n)C(═O)—R⁴; m is 1, 2, or 3; n is 0, 1, or 2; R⁴ is H,C₁-C₈ alkyl substituted with 0-3 R^(4a), C₂-C₈ alkenyl substituted with0-3 R^(4a), C₂-C₈ alkynyl substituted with 0-3 R^(4a), C₃-C₁₀ carbocyclesubstituted with 0-3 R4b, C₆-C₁₀ aryl substituted with 0-3 R^(4b), or 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from H, OH, F, Cl, Br, I, CF₃, C₁-C₃ alkyl,C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), C₆-C₁₀ aryl substitutedwith 0-3 R^(4b), and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(4b); R^(4b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵and R^(5a) are combined to form a 3-8 membered carbocyclic moiety;wherein said 3-8 membered carbocyclic moiety is saturated or partiallyunsaturated; wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)₂—, —N═,—NH—, and —N(R²⁰)—; and wherein said 3-8 membered carbocyclic moiety issubstituted with 0-4 R^(5b); additionally, two R^(5b) substituents onadjacent atoms may be combined to form a benzo fused radical; whereinsaid benzo fused radical is substituted with 0-4 R²³; additionally, twoR^(5b) substituents on adjacent atoms may be combined to form a 5 to 6membered heteroaryl fused radical, wherein said 5 to 6 memberedheteroaryl fused radical comprises 1 or 2 heteroatoms selected from N,O, and S; wherein said 5 to 6 membered heteroaryl fused radical issubstituted with 0-3 R²³; additionally, two R_(5b) substituents on thesame or adjacent carbon atoms may be combined to form a C₃-C₆ carbocyclesubstituted with 0-3 R²³; R5b, at each occurrence, is independentlyselected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, NR¹⁵R¹⁶, OR^(14a), C₁-C₄ alkyl, C₂-C₆ alkenyl, alkynyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—, C₃-C₆carbocycle, phenyl, and a 5 to 6 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur; R⁶ is H; C₁-C₆alkyl substituted with 0-3 R^(6a); C₃-C₁₀ carbocycle substituted with0-3 R^(6b); or C₆-C₁₀ aryl substituted with 0-3 R^(6b); R^(6a), at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, CR¹⁴, Cl, F,Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, aryl and CF₃; R^(6b), at each occurrence,is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;R⁷, at each occurrence, is independently H or C₁-C₄ alkyl; R^(7a), ateach occurrence, is independently H or C₁-C₄ alkyl; R^(7b) is H, C₁-C₄alkyl, or (C₁-C₄ alkyl)OC(═O)—; Ring B is a 7 membered lactam, whereinthe lactam is saturated, partially saturated or unsaturated; whereineach additional lactam carbon is substituted with 0-2 R¹¹; and,optionally, the lactam contains a heteroatom selected from —O—, —S—,—S(═O)—, —S(═O)₂—, —N═, —NH—, and —N(R¹⁰)—; additionally, two R¹¹substituents on adjacent atoms may be combined to form a benzo fusedradical; wherein said benzo fused radical is substituted with 0-4 R¹³;additionally, two R¹¹ substituents on adjacent atoms may be combined toform a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6membered heteroaryl fused radical comprises 1 or 2 heteroatoms selectedfrom N, O, and S; wherein said 5 to 6 membered heteroaryl fused radicalis substituted with 0-3 R¹³; additionally, two R¹¹ substituents on thesame or adjacent carbon atoms may be combined to form a C₃-C₆ carbocyclesubstituted with 0-3 R¹³; R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷; C₁-C₆ alkyl optionally substituted with 0-3R^(10a); C₆-C₁₀ aryl substituted with 0-4 R^(10b); C₃-C₁₀ carbocyclesubstituted with 0-3 R^(10b); or 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(10b);R^(10a), at each occurrence, is independently selected from: H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃; aryl substitutedwith 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); and 5to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(10b); R^(10b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹¹, at eachoccurrence, is independently selected from H, C₁-C₄ alkoxy, Cl, F, Br,I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,S(═O)₂NR¹⁸R¹⁹, CF₃; C₁-C₆ alkyl optionally substituted with 0-3 ^(11a);C₆-C₁₀ aryl substituted with 0-3 R^(11b); C₃-C₁₀ carbocycle substitutedwith 0-3 R^(11b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(11b); R^(11a), ateach occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃; phenyl substituted with 0-3R^(11b); C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); and 5 to 6membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(11b); R^(11b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W is a bond or—(CR⁸R^(8a))_(p)—; p is 0, 1, 2, 3, or 4; R⁸ and R^(8a), at eachoccurrence, are independently selected from H, F, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl and C₃-C₈ cycloalkyl; X is a bond; C₆-C₁₀ arylsubstituted with 0-3 R^(Xb); C₃-C₁₀ carbocycle substituted with 0-3R^(Xb); or 5 to 10 membered heterocycle substituted with 0-2 R^(Xb);R^(Xb), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R16, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄halothioalkoxy; Y is a bond or —(CR⁹R^(9a))_(t)-V—(CR⁹R^(9a))_(u)—; t is0, 1, or 2; u is 0, 1, or 2; R⁹ and R^(9a), at each occurrence, areindependently selected from H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; V isa bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—,—NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or —OC(═O)—; Z is H; C₁-C₈alkyl substituted with 0-3 R1^(12a); C₂-C₆ alkenyl substituted with 0-3R^(12a); C₂-C₆ alkynyl substituted with 0-3 R^(12a); C₆-C₁₀ arylsubstituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4R^(12b); or 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R1^(12b); R^(12a), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄haloalkyl-S—, C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₁₀carbocycle substituted with 0-4 R^(12b); and 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, aryl, C₃-C₆ cycloalkyl, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H,phenyl, benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or 3-C₆ cycloalkyl;R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl; R¹⁵, at each occurrence,is independently selected from H, C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁶, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, benzyl, phenethyl,(C₁-C₆ alkyl)-C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—; R¹⁷ is H, C₁-C₆ alkyl,C₂-C₆ alkoxyalkyl, aryl substituted by 0-4 R^(17a), or —CH₂-arylsubstituted by 0-4 R^(17a); R^(17a) is H, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃,S(O)CH₃, SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, aryl,aryl-CH₂—, aryl-CH₂CH₂—, (C₁-C₆ alkyl)—C(⊚O)—, and (C₁-C₆alkyl)—S(═O)₂—; R¹⁹, at each occurrence, is independently selected fromH, OH, C₁-C₆ alkyl, aryl, aryl-CH₂—, aryl-CH₂CH₂—, (C₁-C₆ alkyl)—C(═O)—,and (C₁-C₆ alkyl)—S(═O)₂—; R^(19b), at each occurrence, is independentlyis H or C₁-C₄ alkyl; R²⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷; C₁-C₆ alkyl optionally substituted with 0-3R^(20a); or C₆-C₁₀ aryl substituted with 0-4 R^(20b); R^(20a), at eachoccurrence, is independently selected from H, C₁-C₄ alkyl, OR¹⁴, Cl, F,Br, I, ═O, CN, N₂, NR¹⁵R¹⁶, CF₃, and aryl substituted with 0-4 R^(20b);R^(20b), at each occurrence, is independently selected from H, OH, Cl,F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; and R²³, at each occurrence, is independently selectedfrom H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,and CF₃; provided when Q is —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴ and R^(7b) is(C₁-C₄ alkyl)OC(═O)—, then n is 1 or 2; and provided when Q is—(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴ and n is 0, then R⁴ does not contain a—C(═O)— adjacent to —N(R^(7b))—.
 2. A compound, according to claim 1, ofFormula (I) or a stereoisomer, pharmaceutically acceptable salt orprodrug thereof, wherein: Q is —(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(m)—CH(OH)—R⁴, —(CR⁷R^(7a))_(m)—NHC(═O)—R⁴,—(CR⁷R^(7a))_(n)—S—R⁴, —(CR⁷R^(7a))_(n)—O—R⁴, or—(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴; m is 1 or 2; n is 0 or 1; R⁴ is H, C₁-C₈alkyl substituted with 0-3 R^(4a), C₂-C₈ alkenyl substituted with 0-3R^(4a), C₂-C₈ alkynyl substituted with 0-3 R^(4a), C₃-C₁₀ carbocyclesubstituted with 0-3 R^(4b), C₆-C₁₀ aryl substituted with 0-3 R^(4b), or5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from H, OH, F, Cl, Br, I, CF₃, C₁-C₃ alkyl,C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), C₆-C₁₀ aryl substitutedwith 0-3 R^(4b), and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(4b); R^(4b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵and R^(5a) are combined to form a 3-8 membered carbocyclic moiety;wherein said 3-8 membered carbocyclic moiety is saturated or partiallyunsaturated; wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and whereinsaid 3-8 membered carbocyclic moiety is substituted with 0-4 R^(5b);additionally, two R^(5b) substituents on adjacent atoms may be combinedto form a benzo fused radical; wherein said benzo fused radical issubstituted with 0-4 R²³; additionally, two R^(5b) substituents onadjacent atoms may be combined to form a 5 to 6 membered heteroarylfused radical, wherein said 5 to 6 membered heteroaryl fused radicalcomprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5to 6 membered heteroaryl fused radical is substituted with 0-3 R²³;additionally, two R^(5b) substituents on the same or adjacent carbonatoms may be combined to form a C₃-C₆ carbocycle substituted with 0-3R²³; R^(5b), at each occurrence, is independently selected from H, OH,Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶,OR^(14a), C₁-C₄ alkyl, C₂-C₆ alkenyl, alkynyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—, C₃-C₆ carbocycle,phenyl, and a 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur; R⁶ is H, methyl, or ethyl;R⁷, at each occurrence, is independently H or C₁-C₄ alkyl; R^(7a), ateach occurrence, is independently H or C₁-C₄ alkyl; R^(7b) is H, C₁-C₄alkyl, or (C₁-C₄ alkyl)OC(═O)—; Ring B is selected from:

R¹⁰ is H, C(═O)R¹⁷, C (═O) OR¹⁷, C(═O) NR¹⁸R¹⁹, S (═O)₂NR¹⁸R¹⁹,S(═O)₂R¹⁷; C₁-C₆ alkyl optionally substituted with 0-3 R^(10a); C₆-C₁₀aryl substituted with 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with0-3 R^(10b); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(10b); R^(10a), ateach occurrence, is independently selected from: H, C₁-C₆ alkyl, OR¹⁴,Cl, F, Br, I, ═O, CN, N₂, NR¹⁵R¹⁶, CF₃; aryl substituted with 0-4R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); and 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(10b); R^(10b), at each occurrence, isindependently selected from H, OH, C_(1,) F, Br, I, CN, NO₂, NR¹⁵R¹⁶,CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹¹, at eachoccurrence, is independently selected from H, C₁-C₄ alkoxy, Cl, F, Br,I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,S(═O)₂NR¹⁸R¹⁹, CF₃; C₁-C₆ alkyl optionally substituted with 0-3 R^(11a);C₆-C₁₀ aryl substituted with 0-3 R^(11b); C₃-C₁₀ carbocycle substitutedwith 0-3 R^(11b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(11b); R^(11a), ateach occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴,C_(1,) F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃; phenyl substituted with 0-3R^(11b); C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); and 5 to 6membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(11b); R^(11b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W is a bond or—(CH₂)_(p)—; p is 1 or 2; X is a bond; phenyl substituted with 0-2R^(Xb); C₃-C₆ carbocycle substituted with 0-2 R^(Xb); or 5 to 6 memberedheterocycle substituted with 0-2 R^(Xb); R^(Xb), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₃haloalkyl, C₁-C₃ haloalkoxy, and C₁-C₃ halothioalkoxy; Y is a bond,—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)——C(═O)NR^(19b)—,—NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—,—S(═O)NR^(19b)—, —C(═O)O—, or —OC(═O)—; Z is H; C₁-C₈ alkyl substitutedwith 0-3 R^(12a); C₂-C₆ alkenyl substituted with 0-3 R^(12a); C₂-C₆alkynyl substituted with 0-3 R^(12a); C₆-C₁₀ aryl substituted with 0-4R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R1^(12b); R^(12a), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,—C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—,C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substitutedwith 0-4 R^(12b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); R^(12b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl,benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆ cycloalkyl; R^(14a) isH, phenyl, benzyl, or C₁-C₄ alkyl; R¹⁵, at each occurrence, isindependently selected from H, C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—; R¹⁶, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, benzyl, phenethyl,(C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—; R¹⁷ is H, C₁-C₆ alkyl,C₂-C₆ alkoxyalkyl, aryl substituted by 0-4 R^(17a), or —CH₂-arylsubstituted by 0-4 R^(17a); R^(17a) is H, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃,S(O)CH₃, SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, phenyl,benzyl, phenethyl, (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—; R¹⁹,at each occurrence, is independently selected from H, OH, methyl, ethyl,propyl, butyl, phenyl, benzyl, and phenethyl; R^(19b), at eachoccurrence, is independently is H or C₁-C₄ alkyl; R²⁰ is C(═O)OR⁷; R²³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; provided when Qis —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴ and R^(7b) is (C₁-C₄ alkyl)OC(═O)—,then n is 1 or 2; and provided when Q is —(CR⁷R^(7a))_(n)—N(R^(7b))—R⁴and n is 0, then R⁴ does not contain a —C(═O)— adjacent to —N(R^(7b))—.3. A compound, according to claim 2, of Formula (Ia):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof,wherein: Q is —(CHR^(7a))_(m)—R⁴, —(CHR^(7a))_(m)—CH(OH)—R⁴,—(CHR^(7a))_(m)—NHC(═O)—R⁴, —(CHR^(7a))_(n)—S—R⁴, —(CHR^(7a))_(n)—O—R⁴,or —(CHR^(7a))_(n)—N(R^(7b))—R⁴; m is 1 or 2; n is 0 or 1; R⁴ is H,C₁-C₈ alkyl substituted with 0-3 R^(4a), C₂-C₈ alkenyl substituted with0-3 R^(4a), C₂-C₈ alkynyl substituted with 0-3 R^(4a), C₃-C₁₀ carbocyclesubstituted with 0-3 R^(4b), C₆-C₁₀ aryl substituted with 0-3 R^(4b), or5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from H, OH, F, Cl, Br, I, CF₃, methyl, ethyl,C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), C₆-C₁₀ aryl substitutedwith 0-3 R^(4b), and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(4b); R^(4b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵and R^(5a) are combined to form a 3-8 membered carbocyclic moiety;wherein said 3-8 membered carbocyclic moiety is saturated or partiallyunsaturated; wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and whereinsaid 3-8 membered carbocyclic moiety is substituted with 0-4 R^(5b);additionally, two R^(5b) substituents on adjacent atoms may be combinedto form a benzo fused radical; wherein said benzo fused radical issubstituted with 0-4 R²³; additionally, two R^(5b) substituents onadjacent atoms may be combined to form a 5 to 6 membered heteroarylfused radical, wherein said 5 to 6 membered heteroaryl fused radicalcomprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5to 6 membered heteroaryl fused radical is substituted with 0-3 R²³;additionally, two R^(5b) substituents on the same or adjacent carbonatoms may be combined to form a C₃-C₆ carbocycle substituted with 0-3R²³; R^(5b), at each occurrence, is independently selected from H, OH,Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶,OR^(14a), C₁-C₄ alkyl, C₂-C₆ alkenyl, alkynyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—, C₃-C₆ carbocycle,phenyl, and a 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur; R^(7a), at each occurrence,is independently H, methyl, or ethyl; R^(7b) is H, methyl, ethyl,CH₃OC(═O)—, or CH₃CH₂OC(═O)—; Ring B is selected from:

R¹¹, at each occurrence, is independently selected from H, C₁-C₄ alkoxy,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,S(═O)₂NR¹⁸R¹⁹, CF₃; C₁-C₆ alkyl optionally substituted with 0-3 R^(11a);C₆-C₁₀ aryl substituted with 0-3 R^(11b); C₃-C₁₀ carbocycle substitutedwith 0-3 R^(11b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(11b); R^(11a), ateach occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃; phenyl substituted with 0-3R^(11b); C₃-C₆ cycloalkyl substituted with 0-3 R^(11b); and 5 to 6membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(11b); R^(11b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W is a bond; X is abond; Y is a bond; Z is H; C₁-C₈ alkyl substituted with 0-3 R^(12a);C₂-C₆ alkenyl substituted with 0-3 R^(12a); C₂-C₆ alkynyl substitutedwith 0-3 R^(12a); C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₁₀carbocycle substituted with 0-4 R^(12b); or 5 to 10 membered heterocyclecontaining 1 to 4 heteroatoms selected from nitrogen, oxygen, andsulphur, wherein said 5 to 10 membered heterocycle is substituted with0-3 R^(12b); R^(12a), at each occurrence, is independently selected fromH, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, C₁-C₄ haloalkyl-S—, C₆-C₁₀ aryl substituted with 0-4R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, N02, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl,benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆ cycloalkyl; R^(14a) isH, phenyl, benzyl, or C₁-C₄ alkyl; R¹⁵ at each occurrence, isindependently selected from H, C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₆alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—; R¹⁶, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, benzyl, phenethyl,(C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—; R¹⁷ is H, C₁-C₆ alkyl,C₂-C₆ alkoxyalkyl, aryl substituted by 0-4 R^(7a), or CH₂-arylsubstituted by 0-4 R^(17a); R^(17a) is H, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃,S(O)CH₃, SO₂CH₃, —NH₂, -N(CH₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, phenyl,benzyl, phenethyl, (C₁-C₆ alkyl)—C(═O)—, and (C₁-C₆ alkyl)—S(═O)₂—; R¹⁹,at each occurrence, is independently selected from H, OH, methyl, ethyl,propyl, butyl., phenyl, benzyl, and phenethyl; R²³, at each occurrence,is independently selected from H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; provided when Q is—(CHR^(7a))_(n)—N(R^(7b))—R⁴ and R^(7b) is (C₁-C₄ alkyl)OC(═O)—, then nis 1 or 2; and provided when Q is —(CHR^(7a))_(n)—N(R^(7b))—R⁴ and n is0, then R⁴ does not contain a —C(═O)— adjacent to —N(R^(7b))—.
 4. Acompound according to claim 3 of Formula (Ia) or a stereoisomer,pharmaceutically acceptable salt or prodrug thereof, wherein: Q is—(CH₂)_(m)—R⁴, —(CH₂)_(m)—CH(OH)—R⁴, —(CH₂)_(m)—NHC (═O)—R⁴,—(CH₂)_(n)—S—R⁴, —(CH₂)_(n)—O—R⁴, or —(CH₂)_(n)—N(R^(7b))—R⁴; m is 1 or2; n is 0 or 1; R⁴ is C₁-C₈ alkyl substituted with 0-3 R^(4a), C₂-C₈alkenyl substituted with 0-3 R^(4a), C₂-C₈ alkynyl substituted with 0-3R^(4a), C₃-C₁₀ carbocycle substituted with 0-3 R^(4b), C₆-C₁₀ arylsubstituted with 0-3 R^(4b), or 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(4b);R^(4a), at each occurrence, is independently selected from H, OH, F, Cl,Br, I, CF₃, methyl, C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),C₆-C₁₀ aryl substituted with 0-3 R^(4b), and 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(4b); R^(4b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵ and R^(5a) arecombined to form a 3-8 membered carbocyclic moiety; wherein said 3-8membered carbocyclic moiety is saturated or partially unsaturated;wherein said 3-8 membered carbocyclic moiety may optionally contain aheteroatom selected from —O—, —NH—, and —N(R²⁰)—; and wherein said 3-8membered carbocyclic moiety is substituted with 0-3 R^(5b); R^(5b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^(14a), C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R^(7b) is H, methyl, ethyl,CH₃OC(═O)—, or CH₃CH₂OC(═O)—; Ring B is selected from:

R¹¹, at each occurrence, is independently selected from H, ═O, NR¹⁸R¹⁹,CF₃; C₁-C₄ alkyl optionally substituted with 0-1 R¹¹a; phenylsubstituted with 0-3 R^(11b); C₃-C₆ carbocycle substituted with 0-3R^(11b); and 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl; R^(11a), at each occurrence, is independently selected fromH, C₁-C₄ alkyl, OR¹⁴, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substitutedwith 0-3 R^(11b) R^(11b), at each occurrence, is independently selectedfrom H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; W is a bond; Xis a bond; Y is a bond; Z is H; C₁-C₈ alkyl substituted with 0-3 R^(2a);C₂-C₆ alkenyl substituted with 0-3 R^(12a); or C₂-C₆ alkynyl substitutedwith 0-3 R^(12a); R^(12a), at each occurrence, is independently selectedfrom H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl,SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—, C₆-C₁₀ aryl substituted with 0-4R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(12b); and wherein said 5 to 10 memberedheterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl,thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl,and isoquinolinyl; R^(12b), at each occurrence, is independentlyselected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br,I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl,C₂-C₆ alkoxyalkyl, or C₃-C₆ cycloalkyl; R^(14a) is H, phenyl, benzyl, orC₁-C₄ alkyl; R¹⁵, at each occurrence, is independently selected from H,C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)—C(═O)—, and (C₁-C₄alkyl)—S(═O)₂—; R¹⁶, at each occurrence, is independently selected fromH, OH, C₁-C₆ alkyl, benzyl, phenethyl, (C₁-C₄ alkyl)—C(═O)—, and (C₁-C₄alkyl)—S(═O)₂—; R¹⁸, at each occurrence, is independently selected fromH, C₁-C₆ alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)—C(═O)—, and(C₁-C₆ alkyl)—S(═O)₂—; R¹⁹, at each occurrence, is independentlyselected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl; provided when Q is —(CH₂)_(n)—N(R^(7b))—R⁴ and R^(7b) is(C₁-C₄ alkyl)OC(═O)—, then n is 1 or 2; and provided when Q is—(CH₂)_(n)—N(R^(7b))—R⁴ and n is O, then R⁴ does not contain a —C(═O)—adjacent to —N(R^(7b))—.
 5. A compound according to claim 4 wherein: Qis —CH₂R⁴, —CH₂CH₂R⁴, —CH₂CH(OH)—R⁴, —CH₂NH—R⁴, —CH₂CH₂NHR⁴,—CH₂N(R^(7b))—R⁴, —CH₂NHC (═O)—R⁴, or —NH—R⁴; R⁴ is C₁-C₆ alkylsubstituted with 0-3 R^(4a), C₂-C₆ alkenyl substituted with 0-3 R^(4a),C₂-C₆ alkynyl substituted with 0-3 R^(4a), C₃-C₆ carbocycle substitutedwith 0-3 R^(4b), phenyl substituted with 0-3 R^(4b), or 5 to 6 memberedheterocycle containing 1 to 3 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from H, OH, F, Cl, Br, I, CF₃, methyl, C₃-C₆carbocycle substituted with 0-3 R^(4b), phenyl substituted with 0-3R^(4b), and 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(4b); R^(4b), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵and R^(5a) are combined to form a 3-6 membered carbocyclic moiety;wherein said 3-6 membered carbocyclic moiety is saturated or partiallyunsaturated; wherein said 3-6 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and whereinsaid 3-6 membered carbocyclic moiety is substituted with 0-2 R^(5b);R^(5b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, CF₃, acetyl, SCH₃, methyl, ethyl, methoxy, ethoxy,allyl, —OCF₃, and —SCF₃; R^(7b) is H, methyl, ethyl, CH₃OC(═O)13 , orCH₃CH₂0C(═O)—; Ring B is selected from:

R¹¹, at each occurrence, is independently selected from H, ═O, NR¹⁸R¹⁹,CF₃; C₁-C₄ alkyl optionally substituted with 0-1 R^(11a); phenylsubstituted with 0-3 R^(11b); C₃-C₆ carbocycle substituted with 0-3R^(11b); and 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl.,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl; R^(11a), at each occurrence, is independently selected fromH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F,Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b); R^(11b),at each occurrence, is independently selected from H, OH, Cl, F,NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; W is a bond; X is a bond; Y is abond; Z is H; C₁-C₄ alkyl substituted with 0-3 R^(2a); C₂-C₄ alkenylsubstituted with 0-3 R^(2a); or C₂-C₄ alkynyl substituted with 0-3R^(12a); R^(12a), at each occurrence, is independently selected from H,OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; R¹³, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁵, at eachoccurrence, is independently selected from H, C₁-C₄ alkyl, and benzyl;R¹⁶, at each occurrence, is independently selected from H, OH, methyl,ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—,methyl-S(═O)₂—, and ethyl-S(═O)₂—; R¹⁸, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, butyl, phenyl,benzyl, and phenethyl; R¹⁹, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, and butyl; and provided when Qis —NH—R⁴, then R⁴ does not contain a —C(═O)— adjacent to —N(R^(7b))—.6. A compound according to claim 5 or a stereoisomer, pharmaceuticallyacceptable salt or prodrug thereof wherein: Q is —CH₂R⁴, —CH₂CH₂R⁴,—CH₂CH(OH)—R⁴, —CH₂NH—R⁴, —CH₂CH₂NHR⁴, —CH₂N(R^(7b))—R⁴, -CH₂NHC(═O)—R⁴,or —NH—R⁴; R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a), C₂-C₆ alkenylsubstituted with 0-3 R^(4a), C₂-C₆ alkynyl substituted with 0-3 R^(4a),C₃-C₆ carbocycle substituted with 0-3 R^(4b), or phenyl substituted with0-3 R^(4b); R^(4a), at each occurrence, is independently selected fromH, OH, F, Cl, Br, I, CF₃, methyl, C₃-C₆ carbocycle substituted with 0-3R^(4b), phenyl substituted with 0-3 R^(4b), and 5 to 6 memberedheterocycle containing 1 to 3 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-3 R^(4b); wherein said 5 to 6 membered heterocycle isselected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, and tetrazolyl; R^(4b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵ and R⁵a arecombined to form a 3-6 membered carbocyclic moiety selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and perhydro-2H-pyran;wherein said 3-6 membered carbocyclic moiety is substituted with 0-1R^(5b); R^(5b) is selected from H, OH, Cl, F, CN, CF₃, methyl, ethyl,methoxy, ethoxy, allyl, and —OCF₃; R^(7b) is H, methyl, ethyl, CH₃OC(═O)—, or CH₃CH₂OC(═O)—; Ring B is selected from:

R¹¹, at each occurrence, is independently selected from H, ═O, NR¹⁸R¹⁹;C₁-C₄ alkyl optionally substituted with 0-1 R^(11a); phenyl substitutedwith 0-3 R^(11b); 5 to 6 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 6 membered heterocycle is substituted with 0-3 R^(11b); wherein said5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl; R^(11a), at each occurrence, is independently selected fromH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O,NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b); R^(11b), at eachoccurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃,methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl,and C₁-C₂ haloalkoxy; W is a bond; X is a bond; Y is a bond; Z is H;C₁-C₄ alkyl substituted with 0-1 R^(12a); C₂-C₄ alkenyl substituted with0-1 R^(12a); or C₂-C₄ alkynyl substituted with 0-1 R^(12a); R^(12a), ateach occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶,CF₃, acetyl, SCH₃, S (═O) CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; R¹³, ateach occurrence, is independently selected from H, OH, methyl, ethyl,propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃; R¹⁵, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; R¹⁶, at each occurrence, is independently selectedfrom H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl; R¹⁸, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, butyl, phenyl, benzyl, and phenethyl; R¹⁹, at each occurrence,is independently selected from H, methyl, ethyl, propyl, and butyl;provided when Q is —NH—R⁴, then R⁴ does not contain a —C(═O)— adjacentto —N(R^(7b))—.
 7. A compound according to claim 6 wherein: R⁵ andR^(5a) are combined to form cyclopentyl or cyclohexyl; Q is —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH₂CH(CH₃)₂,—CH₂NHCH₂CH₃, —CH₂NHCH₂CH₂CH₃, —CH₂NHCH₂CH₂CH₂CH₃, —CH₂NHCH(CH₃)₂,—CH₂NHCH₂CH(CH₃)₂, —CH₂NHCH₂CH₂CH(CH₃)_(2,) —CH₂CH(OH)CH₂CH₃,—CH₂CH(OH)CH₂CH₂CH₃, —CH₂CH(OH)CH₂CH₂CH₂CH₃, —CH₂CH(OH)CH(CH₃)₂,—CH₂CH(OH)CH₂CH(CH₃)₂, —CH₂CH(OH)CH₂CH₂CH(CH₃)₂, —CH₂CH(cyclopropyl),—CH₂CH₂CH(cyclopropyl), —CH₂CH₂CH₂CH(cyclopropyl),—CH₂N(C(═O)OCH₂CH₃)CH₂CH₂CH(CH₃)₂, —CH₂NHC(═O)—CH₂—(3,5-diF-phenyl),—CH₂NHC(═O)CH(OH)CH(CH₃)₂, —CH₂NHC(═O)CH(OH)CH₂CH (CH₃)₂,—CH₂NHC(═O)CH(OH)CH₂CH₂CH₃, —CH₂NHCH₂CH(OH)CH₂CH(CH₃)₂,—CH₂NHCH₂CH(OH)CH₂CH₂CH₃, —CH₂NHCH₂CH(OH)CH₂CH₂CH₂CH₃,—CH₂NHCH₂CH(OH)CH(CH₃)₂, —CH₂NHCH₂CH₂—(cyclopropyl),—CH₂NHCH₂CH₂—(cyclobutyl), —CH₂NHCH₂CH₂—(cyclopentyl),—CH₂NHCH₂CH₂—(cyclohexyl), —CH₂NHCH₂—(cyclopropyl),—CH₂NHCH₂—(cyclobutyl), —CH₂NHCH₂—(cyclopentyl), —CH₂NHCH₂—(cyclohexyl),—CH₂NH—(cyclopropyl), —CH₂NH—(cyclobutyl), —CH₂NH—(cyclopentyl),—CH₂NH—(cyclohexyl), —CH₂NHCH₂CH₂—(3,5-diF-phenyl),—CH₂NHCH₂—(1,4-diF-phenyl), —CH₂CH₂NHCH₂CH(CH₃)₂, —CH₂CH₂NHCH₂CH₂CH₃,—CH₂CH₂NHCH₂CH₂CH₂CH₃, —CH₂CH₂NHCH₂—(cyclopropyl),—CH₂CH₂NHCH₂—(cyclobutyl), —CH₂CH₂NHCH₂—(cyclopentyl),—CH₂CH₂NHCH₂—(cyclohexyl), —NHCH₂CH(OH)CH(CH3)₂,—NHCH₂CH(OH)—(cyclopropyl), —NHCH₂CH(OH)—(cyclobutyl),—NHCH₂CH(OH)—(cyclopentyl), —NHCH₂CH(OH)—(cyclohexyl), or—CH₂NHCH₂CH(OH)—(phenyl); W is a bond; X is a bond; Y is a bond; Z ismethyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl,or allyl; R¹¹, at each occurrence, is independently selected from H, ═O,methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH₂—,(4-F-phenyl)CH₂CH₂—, 3-F-phenyl, (3-F-phenyl)CH₂—, (3-F-phenyl)CH₂CH₂—,2-F-phenyl, (2-F-phenyl)CH₂—, (2-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,(4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 3-Cl-phenyl, (3-Cl-phenyl)CH₂—,(3-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—,(4-CH₃-phenyl)CH₂CH₂—, 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—,(3-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—,(4-CF₃-phenyl)CH₂CH₂—, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and R¹³ ateach occurrence, is independently selected from H, F, Cl, OH, —CH₃,—CH₂CH₃, —OCH₃, and —CF₃.
 8. A compound according to claim 2 of Formula(I) wherein: Q is —(CH2)_(m)—R⁴, —(CH₂)_(m)—CH(OH)—R⁴,—(CH₂)_(m)—NHC(═O)—R⁴, —CH₂)_(n)—S—R⁴, —(CH₂)_(n)—O—R⁴, or—(CH₂)_(n)—N(R^(7b))—R⁴; m is 1 or 2; n is 0 or 1; R⁴ is C₁-C₈ alkylsubstituted with 0-3 R^(4a), C₂-C₈ alkenyl substituted with 0-3 R^(4a),C₂-C₈ alkynyl substituted with 0-3 R^(4a), C₃-C₁₀ carbocycle substitutedwith 0-3 R^(4b), C₆-C₁₀ aryl substituted with 0-3 R^(4b), or 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from H, OH, F, Cl, Br, I, CF₃, methyl, C₃-C₁₀carbocycle substituted with 0-3 R^(4b), C₆-C₁₀ aryl substituted with 0-3R^(4b), and 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(4b); R^(4a), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵and R^(5a) are combined to form a 3-8 membered carbocyclic moiety;wherein said 3-8 membered carbocyclic moiety is saturated or partiallyunsaturated; wherein said 3-8 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and whereinsaid 3-8 membered carbocyclic moiety is substituted with 0-3 R^(5b);R^(5b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶,OR^(14a), C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R^(7b)is H, methyl,ethyl, CH₃OC(═O)—, or CH₃CH₂OC(═O)—; Ring B is selected from:

R¹¹, at each occurrence, is independently selected from H, ═O, NR¹⁸R¹⁹,CF₃; C₁-C₄ alkyl optionally substituted with 0-1 R^(11a) ; phenylsubstituted with 0-3 R^(11b); C₃-C₆ carbocycle substituted with 0-3R^(11b); and 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl; R^(11a), at each occurrence, is independently selected fromH, C₁-C₄ alkyl, OR¹⁴, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, and phenyl substitutedwith 0-3 R^(11b); R^(11b), at each occurrence, is independently selectedfrom H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; W is a bond,—CH₂—, —CH₂CH₂—; X is a bond; phenyl substituted with 0-2 R^(Xb); C₃-C₆cycloalkyl substituted with 0-2 R^(Xb); or 5 to 6 membered heterocyclesubstituted with 0-2 R^(Xb); R^(Xb), at each occurrence, isindependently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, andC₁-C₂ haloalkoxy; Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—,—N(R¹⁹)—, —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂,—S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or—OC(═O)—; Z is C₁-C₃ alkyl substituted with 1-2 R^(12a); C₆-C₁₀ arylsubstituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-3R^(12b); or 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b); R^(12a), at eachoccurrence, is independently selected from C₆-C₁₀ aryl substituted with0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis substituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl,benzyl, C₁-C₆ alkyl, C₂-C₆ alkoxyalkyl, or C₃-C₆ cycloalkyl; R^(14a) isH, phenyl, benzyl, or C₁-C₄ alkyl; R¹⁵, at each occurrence, isindependently selected from H, C₁-C₆ alkyl, benzyl, phenethyl, (C₁—C₄alkyl)—C(═O)—, and (C₁-C₄ alkyl)—S(═O)₂—; R¹⁶, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, benzyl, phenethyl,(C₁-C₄ alkyl)—C(═O)—, and (C₁-C₄ alkyl)—S(═O)₂—; R¹⁸, at eachoccurrence, is independently selected from H, C₁-C₁ alkyl, phenyl,benzyl, phenethyl, (C₁-C₆ alkyl)—C(═O)—, and (C₁C₆ alkyl)—S(═O)₂—; R¹⁹,at each occurrence, is independently selected from H, OH, methyl, ethyl,propyl, butyl, phenyl, benzyl, and phenethyl; R^(19b), at eachoccurrence, is independently selected from H, methyl, ethyl, propyl,butyl, phenyl, benzyl, and phenethyl; provided when Q is—(CH₂)_(n)—N(R^(7b))—R⁴ and R^(7b) is (C₁-C₄ alkyl)OC(═O)—, then n is 1or 2; and provided when Q is —(CH₂)_(n)(R^(7b))—R⁴ and n is 0, then R⁴does not contain a —C(═O)— adjacent to —N(R^(7b))—.
 9. A compoundaccording to claim 8 of Formula (I) wherein: Q is —CH₂R⁴, —CH₂CH₂—R⁴,—CH₂CH(OH)—R⁴, —CH₂NH—R⁴, —CH₂CH₂NHR⁴, —CH₂N(R^(7b))—R⁴, —CH₂NHC(═O)—R⁴,or —NH—R⁴; R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a), C₂-C₆ alkenylsubstituted with 0-3 R^(4a), C₂-C₆ alkynyl substituted with 0-3 R^(4a),C₃-C₆ carbocycle substituted with 0-3 R^(4b), phenyl substituted with0-3 R^(4b), or 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(4b); R⁴a, at eachoccurrence, is independently selected from H, OH, F, Cl, Br, I, CF₃,methyl, C₃-C₆ carbocycle substituted with 0-3 R^(4b), phenyl substitutedwith 0-3 R^(4b), and 5 to 6 membered heterocycle containing 1 to 3heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 6 membered heterocycle is substituted with 0-3 R^(4b); R^(4b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵and R^(5a) are combined to form a 3-6 membered carbocyclic moiety;wherein said 3-6 membered carbocyclic moiety is saturated or partiallyunsaturated; wherein said 3-6 membered carbocyclic moiety may optionallycontain a heteroatom selected from —O—, —NH—, and —N(R²⁰)—; and whereinsaid 3-6 membered carbocyclic moiety is substituted with 0-2 R^(5b);R^(5b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, CF₃, acetyl, SCH₃, methyl, ethyl, methoxy, ethoxy,allyl, —OCF₃, and —SCF₃; R^(7b) is H, methyl, ethyl, CH₃OC(═O)—, orCH₃CH₂OC(═O)—-; Ring B is selected from:

R¹¹, at each occurrence, is independently selected from H, ═—O, NR¹⁸R¹⁹,CF₃; C₁-C₄ alkyl optionally substituted with 0-1 R^(11a); phenylsubstituted with 0-3 R^(11b); C₃-C₆ carbocycle substituted with 0-3R^(11b); and 5 to 6 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-3 R^(11b); wherein said 5 to6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl; R^(11a), at each occurrence, is independently selected fromH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F,Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b); R^(11b),at each occurrence, is independently selected from H, OH, Cl, F,NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; W is a bond, —CH₂—, —CH₂CH₂—; Xis a bond; phenyl substituted with 0-1 R^(Xb); C₃-C₆ cycloalkylsubstituted with 0-1 R^(Xb); or 5 to 6 membered heterocycle substitutedwith 0-1 R^(Xb); R^(Xb) is selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, methoxy,ethoxy, propoxy, and —OCF₃; Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—; Z is C₁-C₂ alkyl substitutedwith 1-2 R^(12a); C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₁₀carbocycle substituted with 0-3 R^(12b); or 5 to 10 membered heterocyclecontaining 1 to 4 heteroatoms selected from nitrogen, oxygen, andsulphur, wherein said 5 to 10 membered heterocycle is substituted with0-3 R^(12b); R^(12a), at each occurrence, is independently selected fromC₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substitutedwith 0-4 R^(12b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); R^(12b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴ is H, phenyl,benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; R¹⁵, at each occurrence, isindependently selected from H, C₁-C₄ alkyl, and benzyl; R¹⁶, at eachoccurrence, is independently selected from H, OH, methyl, ethyl, propyl,butyl, benzyl, phenethyl, methyl—C(═O)—, ethyl—C(═O)—, methyl—S(═O)₂—,and ethyl—S(═O)₂—; R¹⁸, at each occurrence, is independently selectedfrom H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;R¹⁹, at each occurrence, is independently selected from H, methyl,ethyl, propyl, and butyl; and provided when Q is —(CH₂)_(n)—N(R^(7b))—R⁴and R^(7b) is (C₁-C₄ alkyl)OC(═O)—, then n is 1 or 2; and provided whenQ is —(CH₂)_(n)—N(R^(7b))—R⁴ and n is 0, then R⁴ does not contain a—C(═O)— adjacent to —N(R^(7b))—.
 10. A compound according to claim 9 ofFormula (I) or a stereoisomer, pharmaceutically acceptable salt orprodrug thereof, wherein: Q is —CH₂R⁴, —CH₂CH₂R⁴, —CH₂CH(OH)—R⁴,—CH₂NH—R⁴, —CH₂CH₂NHR⁴, —CH₂N (R^(7b))—R⁴, —CH₂NHC (═O)—R⁴, or —NH—R⁴;R⁴ is C₁-C₆ alkyl substituted with 0-3 R^(4a), C₂-C₆ alkenyl substitutedwith 0-3 R^(4a), C₂-C₆ alkynyl substituted with 0-3 R^(4a), C₃-C₆carbocycle substituted with 0-3 R^(4b), or phenyl substituted with 0-3R^(4b); R^(4a), at each occurrence, is independently selected from H,OH, F, Cl, Br, I, CF₃, methyl, C₃-C₆ carbocycle substituted with 0-3R^(4b), phenyl substituted with 0-3 R^(4b), and 5 to 6 memberedheterocycle containing 1 to 3 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-3 R^(4b); wherein said 5 to 6 membered heterocycle isselected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, and tetrazolyl; R^(4b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁵ and R^(5a) arecombined to form a 3-6 membered carbocyclic moiety selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and perhydro-2H-pyran;wherein said 3-6 membered carbocyclic moiety is substituted with 0-1R^(5b); R⁵b is selected from H, OH, Cl, F, CN, CF₃, methyl, ethyl,methoxy, ethoxy, allyl, and —OCF₃; R^(7b) is H, methyl, ethyl,CH₃OC(═O)—, or CH₃CH₂OC(═O)—; Ring B is selected from:

R¹¹, at each occurrence, is independently selected from H, ═O, NR¹⁸R¹⁹;C₁-C₄ alkyl optionally substituted with 0-1 R^(11a); phenyl substitutedwith 0-3 R^(11b); 5 to 6 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 6 membered heterocycle is substituted with 0-3 R^(11b); wherein said5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl; R^(11a), at each occurrence, is independently selected fromH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O,NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^(11b); R^(11b), at eachoccurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃,methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl,and C₁-C₂ haloalkoxy; W is a bond or —CH₂—; X is a bond; phenylsubstituted with 0-1 R^(Xb); C₃-C₆ cycloalkyl substituted with 0-1R^(Xb); or 5 to 6 membered heterocycle substituted with 0-1 R^(Xb);R^(Xb) is selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, methyl,ethyl, methoxy, ethoxy, and —OCF₃; Y is a bond, —C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—; Z is C₁-C₂ alkylsubstituted with 1-2 R^(12a); C₆-C₁₀ aryl substituted with 0-4 R^(12b);C₃-C₁₀ carbocycle substituted with 0-3 R^(12b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(12b); R^(12a), at each occurrence, isindependently selected from C₆-C₁₀ aryl substituted with 0-4 R^(12b);C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); and 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(12b); and wherein said 5 to 10 memberedheterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl,thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl,and isoquinolinyl; R^(12b), at each occurrence, is independentlyselected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and—OCF₃; R¹³, at each occurrence, is independently selected from H, OH,methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR¹⁵R¹⁶,and CF₃; R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl; R¹⁵,at each occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; R16, at each occurrence, is independently selectedfrom H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl; R¹⁸, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, butyl, phenyl, benzyl, and phenethyl; R¹⁹, at each occurrence,is independently selected from H, methyl, ethyl, propyl, and butyl; andprovided when Q is —NH—R⁴, then R⁴ does not contain a —C(═O)— adjacentto —N(R^(7b))—.
 11. A compound, according to claim 10, wherein: R⁵ andR⁵a are combined to form cyclopentyl or cyclohexyl; Q is —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH(CH₃)₂,—CH₂CH₂CH₂CH₂CH(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂NHCH₂CH₂CH₃,—CH₂NHCH₂CH₂CH₂CH₃, —CH₂NHCH(CH₃)₂, —CH₂NHCH₂CH(CH₃)₂,—CH₂NHCH₂CH₂CH(CH₃)₂, —CH₂CH(OH)CH₂CH₃, —CH₂CH(OH)CH₂CH₂CH₃,—CH₂CH(OH)CH₂CH₂CH₂CH₃, —CH₂CH(OH)CH(CH₃)₂, —CH₂CH(OH)CH₂CH(CH₃)₂ ,—CH₂CH(OH)CH₂CH₂CH(CH₃)₂, —CH₂CH(cyclopropyl), —CH₂CH₂CH(cyclopropyl),—CH₂CH₂CH₂CH(cyclopropyl), —CH₂N (C (═O) OCH₂CH₃)CH₂CH₂CH(CH₃)₂,—CH₂NHC(═O)—CH₂—(3,5-diF-phenyl), —CH₂NHC(═O)CH(OH)CH(CH₃)₂,—CH₂NHC(═O)CH(OH)CH₂CH(CH₃)₂, —CH₂NHC (═O)CH(OH) CH₂CH₂CH₃,—CH₂NHCH₂CH(OH)CH₂CH(CH₃)₂, —CH₂NHCH₂CH(OH)CH₂CH₂CH₃,—CH₂NHCH₂CH(OH)CH₂CH₂CH₂CH₃, —CH₂NHCH₂CH(OH)CH(CH₃)₂,—CH₂NHCH₂CH₂—(cyclopropyl), —CH₂NHCH₂CH₂—(cyclobutyl),—CH₂NHCH₂CH₂—(cyclopentyl), —CH₂NHCH₂CH2—(cyclohexyl),—CH₂NHCH₂—(cyclopropyl), —CH₂NHCH₂—(cyclobutyl),—CH₂NHCH₂—(cyclopentyl), —CH₂NHCH2—(cyclohexyl), —CH₂NH—(cyclopropyl),—CH₂NH—(cyclobutyl), —CH₂NH—(cyclopentyl), —CH₂NH—(cyclohexyl),—CH₂NHCH₂CH₂—(3,5-diF-phenyl), —CH₂NHCH2—(1,4-diF-phenyl),—CH₂CH₂NHCH₂CH(CH₃)₂, —CH₂CH₂NHCH₂CH₂CH₃, —CH₂CH₂NHCH₂CH₂CH₂CH₃,—CH₂CH₂NHCH₂—(cyclopropyl), —CH₂CH₂NHCH₂—(cyclobutyl),—CH₂CH₂NHCH₂—(cyclopentyl), —CH₂CH₂NHCH₂—(cyclohexyl),—NHCH₂CH(OH)CH(CH₃)₂, —NHCH₂CH(OH)—(cyclopropyl),—NHCH₂CH(OH)—(cyclobutyl), —NHCH₂CH(OH)—(cyclopentyl),—NHCH₂CH(OH)—(cyclohexyl), or —CH₂NHCH₂CH(OH)—(phenyl); W is a bond or—CH₂—; X is a bond;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or —N(CH₃)—, Zis phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl,4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl,2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl,2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl,3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl,2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl,4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl,3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl,3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl,1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholino, N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—,(3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂,(4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂, (2,4-diF-phenyl)CH₂—,(2,5-diF-phenyl)CH₂—, (2,-diF-phenyl)CH₂—, (3,-diF-phenyl)CH₂—,(3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,(2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,(3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,(3-Cl-4-F-phenyl)CH₂-, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,(4-MeO-phenyl)CH₂—, (2-Me-phenyl) CH₂—, (3-Me-phenyl)CH₂—,(4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,(4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—,(4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—,(thienyl)CH₂—, (pyridyl)CH₂—,(2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—,(1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—,(1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—,(cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—,(N-pipridinyl)CH₂—, phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—,(2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,(2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,(2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,(2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,(3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,(2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,(2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,(3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,(3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—,(3-Cl-4-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—,(4-MeO-phenyl)CH₂CH₂—, (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—,(4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—,(4-MeS-phenyl)CH₂CH₂—, (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,(4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—,(thienyl)CH₂CH₂—,(pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,(4-Me-pyridyl)CH₂CH₂-, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,(isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—,(cyclopropyl)CH₂CH₂—,(cyclobutyl)CH₂CH₂—,(cyclopentyl)CH₂CH₂—,(cyclohexyl)CH₂CH₂—,(morpholino)CH₂CH₂—, or (N-pipridinyl)CH₂CH₂—; R¹¹,at each occurrence, is independently selected from H, ═O, methyl, ethyl,phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH₂—,(4-F-phenyl)CH₂CH₂—, 3-F-phenyl, (3-F-phenyl)CH₂—, (3-F-phenyl)CH₂CH₂—,2-F-phenyl, (2-F-phenyl)CH₂—, (2-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,(4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 3-Cl-phenyl, (3-Cl-phenyl)CH₂—,(3-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—,(4-CH₃-phenyl)CH₂CH₂—, 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—,(3-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—,(4-CF₃-phenyl)CH₂CH₂—, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and R¹³,at each occurrence, is independently selected from H, F, Cl, OH, —CH₃,—CH₂CH₃, —OCH₃, and —CF₃.
 12. A compound according to one of claims 4-11of Formula (Ic):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.13. A compound according to one of claims 4-11 of Formula (Id):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.14. A compound according to one of claims 4-11 of Formula (Ie):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.15. A compound according to one of claims 4-11 of Formula (If):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.16. A compound according to claim 1 selected from:1-{[(3-methylbutyl)amino]methyl}-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclicamide;1-{[N′-(ethoxycarbonyl)-N′-(3-methylbutyl)amino]methyl}-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclicamide;4-{[(3-methylbutyl)amino]methyl}-4-{N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]carbamoyl}-perhydro-2H-pyran;1-(2-hydroxy-pentyl)-N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]-cyclopentanecarbocyclicamide;4-{[[(3,5-difluorophenyl)methyl]amido]methyl}-4-{N-[6,7-dihydro-5-methyl-6-oxo-5H-dibenzo[b,d]azepin-7-yl]carbamoyl}-perhydro-2H-pyran;2-(S)-hydroxy-3-methyl-N-({[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl)butanamide;2-(S)-hydroxy-4-methyl-N-({[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl)pentanamide;2-(3,5-difluorophenyl)-N-({[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}methyl)acetamide;N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))({2-[(2-methylpropyl)amino]ethyl}cyclopentyl)carboxamide;({2-[(cyclopropylmethyl)amino]ethyl}cyclopentyl)-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;[({[2-(3,5-difluorophenyl)ethyl]amino}methyl)cyclopentyl]-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;[({[(1,4-difluorophenyl)methyl]amino}methyl)cyclopentyl]-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;({[(2-cyclopentylethyl)amino]methyl}cyclopentyl)-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;{[((2S)-2-hydroxy-4-methylpentyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;{[((2S)-2-hydroxy-3-methylbutyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;and{[((2S)-2-cyclohexyl-2-hydroxyethyl)amino]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide.17. A compound according to claim 1 selected from:1-{[(3-methylbutylamino]methyl}-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl]-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylicamide;1-(5-methyl)hexyl-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylicamide;1-pentyl-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylicamide;1-(2-hydroxypentyl)-N-{(S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl}-cyclopentanecarbocylicamide;2-(S)-hydroxy-3-methyl-N-{[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]methyl}butanamide;(2S)-N-({[N-(7-fluoro-1-methyl-2-oxo-5-phenyl(3H-benzo[f]l,4-diazepin-3-yl))carbamoyl]cyclopentyl}methyl)-2-hydroxy-3-methylbutanamide;(2S)-N-({[N-(5-cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}methyl)-2-hydroxy-3-methylbutanamide;{[(cyclohexylamino)methyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;({[(2-hydroxyhexyl)amino]methyl}cyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;({[((2R)-2-hydroxy-2-phenylethyl)amino]methyl}cyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]l,4-diazepin-3-yl)}carboxamide;and({[((2S)-2-hydroxy-2-phenylethyl)amino]methyl}cyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]l,4-diazepin-3-yl)}carboxamide.18. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 19. A method for the treatment ofneurological disorders associated with β-amyloid production comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of claim
 1. 20. A method for inhibitingγ-secretase activity comprising administering to a host in need of suchinhibition a therapeutically effective amount of a compound of claim 1that inhibits γ-secretase activity.